TWI744225B - Tyk2 inhibitors and uses thereof - Google Patents

Abstract

The present invention provides compounds, compositions thereof, and methods of using the same for the inhibition of TYK2, and the treatment of TYK2-mediated disorders.

Description

Tyrosine protein kinase 2 (TYK2) inhibitor and its use

The present invention relates to compounds and methods that can be used to inhibit non-receptor tyrosine protein kinase 2 ("TYK2") (also known as tyrosine kinase 2). The present invention also provides pharmaceutically acceptable compositions containing the compounds of the present invention and methods of using the compositions to treat various diseases.

In recent years, a better understanding of the structure of enzymes and other biomolecules associated with diseases has greatly facilitated the search for new therapeutic agents. One class of important enzymes that has been the subject of extensive research is the protein kinase family.

Protein kinases constitute a large family of structurally related enzymes responsible for controlling various signal transduction processes in cells. It is believed that protein kinases evolved from common ancestor genes due to the conservation of their structure and catalytic function. Almost all kinases contain similar 250 to 300 amino acid catalytic domains. Kinases can be classified into different families by their phosphorylated substrates (eg, protein-tyrosine, protein-serine/threonine, lipid, etc.).

Generally speaking, protein kinases mediate intracellular signal transmission by achieving the transfer of phosphate groups from nucleoside triphosphates to protein receptors involved in the signal transmission pathway. These phosphating events act as molecular turn-on/turn-off switches, which can regulate or regulate the biological functions of the target protein. These phosphating events are ultimately triggered in response to a variety of extracellular and other stimuli. Examples of these stimuli include environmental and chemical stress signals (such as osmotic shock, thermal shock, ultraviolet radiation, bacterial endotoxin and H ₂ O ₂ ), cytokines (such as interleukin-1 (IL-1), interleukin-1 (IL-1), IL-8 (IL-8) and tumor necrosis factor alpha (TNF-α)) and growth factors (such as granulocyte macrophage colony stimulating factor (GM-CSF) and fibroblast growth factor (FGF)). Extracellular stimulation can affect one or more cellular responses related to cell growth, migration, differentiation, hormone secretion, transcription factor activation, muscle contraction, glucose metabolism, protein synthesis control, and cell cycle regulation.

Many diseases are associated with abnormal cellular responses triggered by events mediated by kinases. These diseases include (but are not limited to) autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neuropathy and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer's disease (Alzheimer's disease) ) And hormone-related diseases. Therefore, there is still a need to find protein kinase inhibitors that can be used as therapeutic agents.

It has now been found that the compounds of the present invention and their pharmaceutically acceptable compositions can be effectively used as inhibitors of TYK2 kinase.

The compounds of the present invention and their pharmaceutically acceptable compositions can be used to treat various diseases, disorders, or conditions related to the regulation of the signal transmission pathway of TYK2 kinase. Such diseases, disorders or conditions include those described herein.

The compounds provided herein can also be used in the study of TYK2 enzymes in biological and pathological phenomena; the study of intracellular signal transduction pathways that occur in body tissues; and novel TYK2 inhibitors or kinases, signal transduction pathways, and in vitro or in vivo studies. Comparative evaluation of other regulators of cytokine levels in vivo.

1. General description of some embodiments of the present invention:

The compounds of the present invention and their compositions can be used as inhibitors of TYK2 protein kinase.

The binding pocket of TYK2 contains multiple hydration sites, each of which is covered by a single water molecule occupy. Each of these water molecules has a stability rating associated with it. As used herein, the term "stability rating" refers to numerical calculations that include the enthalpy, entropy, and free energy values associated with each water molecule. This stability rating allows measurable determination of the relative stability of the water molecules occupying the hydration site in the binding pocket of TYK2.

If the water molecule occupying the hydration site in the binding pocket of TYK2 has a stability rating of >2.5kcal/mol, it is called "unstable water".

Without wishing to be bound by any particular theory, it is believed that the inhibitor replaces or destroys unstable water molecules (ie, water molecules with a stability rating of >2.5kcal/mol), or replaces stable water (ie, a stability rating of < 1kcal/mol water molecule) causes the inhibitor to bind more tightly. Therefore, compared with inhibitors that do not replace unstable water molecules, the ones designed to replace one or more unstable water molecules (that is, the unstable water molecules that have not been replaced by any known inhibitors) will be more effective. A tight binding agent, and therefore a more potent inhibitor.

It was unexpectedly discovered that the provided compound replaces or destroys one or more unstable water molecules. In some embodiments, the provided compound replaces or destroys at least two unstable water molecules.

或其醫藥上可接受之鹽，其中X、Y、環A、L¹、R¹、R^1’、R³、R⁴及R⁵各自係如下文所定義及如本文實施例中所述，單獨地及組合地。 In certain embodiments, the present invention provides a compound of formula I :

Or a pharmaceutically acceptable salt thereof, wherein X, Y, ring A, L ¹ , R ¹ , R ^{1 '} , R ³ , R ⁴ and R ⁵ are each as defined below and as described in the Examples herein, Individually and in combination.

或其醫藥上可接受之鹽，其中X、Y、環A、L^1’、R¹、R^1’、R³、R⁴及R⁵各自係如下文所定義及如本文實施例中所述，單獨地及組合地。 In certain embodiments, the present invention provides a compound of formula II :

Or a pharmaceutically acceptable salt thereof, wherein X, Y, ring A, L ^{1 '} , R ¹ , R ^1' , R ³ , R ⁴ and R ⁵ are each as defined below and as described in the Examples herein , Individually and in combination.

或其醫藥上可接受之鹽，其中X、Y、環A、L¹、R¹、R^1’、R³、R^4’及R⁵各自係如下文所定義及如本文實施例中所述，單獨地及組合地。 In certain embodiments, the present invention provides a compound of formula III :

Or a pharmaceutically acceptable salt thereof, wherein X, Y, ring A, L ¹ , R ¹ , R ^{1 '} , R ³ , R ^4' and R ⁵ are each as defined below and as described in the Examples herein , Individually and in combination.

或其醫藥上可接受之鹽，其中X、Y、環A、L¹、R³、R⁴及R⁵各自係如下文所定義及如本文實施例中所述，單獨地及組合地。 In certain embodiments, the present invention provides a compound of formula IV :

Or a pharmaceutically acceptable salt thereof, wherein X, Y, ring A, L ¹ , R ³ , R ⁴ and R ⁵ are each as defined below and as described in the Examples herein, individually and in combination.

2. Compound and definition:

The compounds of the present invention include those generally described herein, and are further illustrated by the classes, subclasses, and types disclosed herein. As used herein, unless otherwise indicated, the following definitions will apply. For the purpose of the present invention, the chemical elements are determined according to the CAS version of the Periodic Table of the Elements, Handbook of Chemistry and Physics, 75th edition. Certainly. In addition, the general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999 and "March's Advanced Organic Chemistry" 5th edition, edited by Smith, MB and March, J., John Wiley & Sons, New York: 2001, the entire contents of these documents are incorporated herein by reference.

As used herein, the term "aliphatic" or "aliphatic group" means a substituted or unsubstituted, fully saturated or straight chain (ie, unbranched) or branched chain containing one or more unsaturated units Chain hydrocarbon chain, or fully saturated or containing one or more unsaturated units, but not aromatic monocyclic hydrocarbon or bicyclic hydrocarbon (also referred to herein as "carbocyclic", "cycloaliphatic" or "cycloalkyl") , Which has a single attachment point to the rest of the molecule. Unless otherwise indicated, aliphatic groups contain 1 to 6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1 to 5 aliphatic carbon atoms. In other embodiments, the aliphatic group contains 1 to 4 aliphatic carbon atoms. In other embodiments, the aliphatic group contains 1 to 3 aliphatic carbon atoms, and in other embodiments, the aliphatic group contains 1 to 2 aliphatic carbon atoms. In some embodiments, "cycloaliphatic" (or "carbocyclic" or "cycloalkyl") refers to a monocyclic C ₃ -C _{6 that is fully saturated or contains one or more unsaturated units, but is not aromatic} Hydrocarbons, which have a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, substituted or unsubstituted linear or branched alkyl, alkenyl, alkynyl and mixed forms, such as (cycloalkyl)alkyl, (cycloalkenyl) ) Alkyl or (cycloalkyl)alkenyl.

As used herein, the term "bridged bicyclic ring" refers to any saturated or partially unsaturated bicyclic ring system having at least one bridge, that is, carbocyclic or heterocyclic ring. As defined by IUPAC, "bridge" is an unbranched chain of atoms or an atom or valence bond connecting two bridgeheads, where "bridgehead" is the bond of a ring system to three or more main chain atoms (excluding hydrogen) Any main chain atom. In some embodiments, a bridged bicyclic group has 7 to 12 ring members and 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. These bridged bicyclic groups are well known in the art and include the groups listed below, where each group is attached to the remainder of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise indicated, bridged bicyclic groups are optionally substituted with one or more substituents as listed for aliphatic groups. Additionally or alternatively, any replaceable nitrogen of the bridging bicyclic group is optionally substituted. Exemplary bridged double rings include:

The term "lower carbon number alkyl" refers to C _1-4 straight or branched chain alkyl. Exemplary alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tertiary butyl.

The term "lower-carbon haloalkyl" refers to a C _1-4 straight or branched chain alkyl substituted with one or more halogen atoms.

The term "heteroatom" means one or more of oxygen, sulfur, phosphorus, or silicon (including any oxidized form of nitrogen, sulfur, phosphorus or silicon; any quaternary ammonium form of basic nitrogen; or heterocyclic Substitutable nitrogen, such as N (as in 3,4-dihydro-2 H -pyrrolyl), NH (as in pyrrolidinyl) or NR ⁺ (as in N-substituted pyrrolidinyl)) .

As used herein, the term "unsaturated" means that a certain part has one or more units of unsaturation.

As used herein, the term "divalent C _1-8 (or C _1-6 ) saturated or unsaturated linear or branched hydrocarbon chain" refers to a divalent linear or branched alkylene chain as defined herein, Alkenylene and alkynylene chains.

The term "alkylene" refers to a divalent alkyl group. The "alkylene chain" is a polymethylene group, namely -(CH ₂ ) _n -, where n is a positive integer, preferably 1 to 6, 1 to 4, 1 to 3, 1 to 2 or 2 To 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced by a substituent. Suitable substituents include those described below for substituted aliphatic groups.

The term "alkenylene" refers to a divalent alkenyl group. A substituted alkenylene chain is a polymethylene group in which one or more hydrogen atoms are replaced by a substituent and contains at least one double bond. Suitable substituents include those described below for substituted aliphatic groups.

。 As used herein, the term "cyclopropylenyl" refers to a divalent cyclopropyl group having the following structure:

.

The term "halogen" means F, Cl, Br or I.

Used alone or as part of a larger part (as in "aralkyl", "aralkoxy" or "aryloxyalkyl" generally) the term "aryl" means a total of five to fourteen A monocyclic or bicyclic ring system of three ring members, wherein at least one ring in the system is aromatic, and wherein each ring in the system contains 3 to 7 ring members. The term "aryl" can be used interchangeably with the term "aryl ring". In certain embodiments of the present invention, "aryl" refers to an aromatic ring system, which includes (but is not limited to) phenyl, biphenyl, naphthyl, anthracenyl, etc., which may have one or more substituents . As used herein, groups in which an aromatic ring is fused to one or more non-aromatic rings are also included within the scope of the term "aryl", such as indenyl, phthalimino , Naphthimidyl, phenanthridinyl or tetrahydronaphthyl, etc.

The terms "heteroaryl" and "heteroaryl-" used alone or as part of a larger part (such as "heteroaralkyl" or "heteroaralkoxy") refer to having 5 to 10 ring atoms, Preferably, 5, 6 or 9 ring atoms; 6, 10 or 14 π electrons are shared in the ring array; and groups with one to five heteroatoms in addition to carbon atoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternary ammonium form of basic nitrogen. Heteroaryl groups include (but are not limited to) thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, Isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indazinyl, purinyl, naphthyridinyl and pterridinyl. The terms "heteroaryl" and "heteroaromatic-" as used herein also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic or heterocyclyl rings, in which a free radical or The attachment point is on the heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquine Linyl, cinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H -quinazolinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, Tetrahydroquinolinyl, tetrahydroisoquinolinyl and pyrido[2,3-b]-1,4-oxazine-3(4H)-one. Heteroaryl groups can be monocyclic or bicyclic. The term "heteroaryl" can be used interchangeably with the terms "heteroaryl ring", "heteroaryl group" or "heteroaromatic", any of which includes optionally substituted rings. The term "heteroaralkyl" refers to an alkyl group substituted with a heteroaryl group, where the alkyl and heteroaryl moieties are independently optionally substituted.

As used herein, the terms "heterocyclic ring", "heterocyclic group", "heterocyclic radical" and "heterocyclic ring" are used interchangeably and refer to saturated or partially unsaturated, and have one or Multiple, preferably one to four stable 5- to 7-membered monocyclic or 7 to 10-membered bicyclic heterocyclic moieties of heteroatoms as defined above. When used in reference to a ring atom of a heterocyclic ring, the term "nitrogen" includes substituted nitrogen. As an example, in a saturated or partially unsaturated ring with 0 to 3 heteroatoms selected from oxygen, sulfur, or nitrogen, the nitrogen can be N (as in 3,4-dihydro- 2H -pyrrolyl, generally ), NH (as in pyrrolidinyl) or ⁺ NR (as in N -substituted pyrrolidinyl).

The heterocyclic ring may be attached to its side group at any heteroatom or carbon atom that results in a stable structure, and any ring atom may optionally be substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include (but are not limited to) tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinoline Group, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolane, diazepanyl, oxazepinyl, thiazolinyl, morpholinyl, 2-oxa-6-azaspiro[3.3]heptane and quinuclidine. The terms "heterocycle", "heterocyclyl", "heterocyclyl ring", "heterocyclic group", "heterocyclic moiety" and "heterocyclic radical" are used interchangeably herein, and include Cyclic ring is a group fused to one or more aryl, heteroaryl or cycloaliphatic rings, such as indolinyl, 3 H -indolyl, chromanyl, phenanthridinyl or tetrahydroquine Linyl. The heterocyclic group may be monocyclic or bicyclic. The term "heterocycloalkyl" refers to an alkyl group substituted with a heterocyclic group, wherein the alkyl and heterocyclyl moieties are independently optionally substituted.

As used herein, the term "partially unsaturated" refers to a ring portion that includes at least one double bond or triple bond. The term "partially unsaturated" is intended to encompass rings with multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties as defined herein.

As used herein, the compounds of the invention may contain "optionally substituted" moieties. Generally speaking, the term "substituted" (regardless of whether the term "as appropriate" is preceded or not) means that one or more hydrogens of the designated part are replaced by suitable substituents. Unless otherwise indicated, a "optionally substituted" group has suitable substituents at each substitutable position of the group, and when more than one position in any given structure can be selected from more than one group When the substituents are substituted, the substituents at each position may be the same or different. The combinations of substituents contemplated by the present invention are preferably those that result in the formation of stable or chemically feasible compounds. As used herein, the term "stable" means that it does not change substantially when subjected to conditions that allow its preparation, detection, and in certain embodiments its recovery, purification, and use for one or more purposes disclosed herein The compound.

Suitable monovalent substituents on substitutable carbon atoms of "optionally substituted" groups are independently halogen; -(CH ₂ ) _0-4 R ^o ; -(CH ₂ ) _0-4 OR ^o ; -O(CH ₂ ) _0-4 R ^o , -O-(CH ₂ ) _0-4 C(O)OR ^o ;-(CH ₂ ) _0-4 CH(OR ^o ) ₂ ;-(CH ₂ ) _0-4 SR ^o ; -(CH ₂ ) _0-4 Ph, which can be ^{substituted by R o} ; -(CH ₂ ) _0-4 O(CH ₂ ) _0-1 Ph, which can be ^{substituted by R o} ; -CH=CHPh, which can be Substituted by R ^o ; -(CH ₂ ) _0-4 O(CH ₂ ) _{0-1 -Pyridyl} , which may be ^{substituted by R o} ; -NO ₂ ; -CN; -N ₃ ; -(CH ₂ ) _{0- 4} N(R ^o ) ₂ ;-(CH ₂ ) _0-4 N(R ^o )C(O)R ^o ;-N(R ^o )C(S)R ^o ;-(CH ₂ ) _0-4 N (R ^o )C(O)NR ^o ₂ ;-N(R ^o )C(S)NR ^o ₂ ;-(CH ₂ ) _0-4 N(R ^o )C(O)OR ^o ;-N(R ^o )N(R ^o )C(O)R ^o ;-N(R ^o )N(R ^o )C(O)NR ^o ₂ ;-N(R ^o )N(R ^o )C(O)OR ^o ; -(CH ₂ ) _0-4 C(O)R ^o ; -C(S)R ^o ; -(CH ₂ ) _0-4 C(O)OR ^o ; -(CH ₂ ) _0-4 C(O )SR ^o ;-(CH ₂ ) _0-4 C(O)OSiR ^o ₃ ;-(CH ₂ ) _0-4 OC(O)R ^o ;-OC(O)(CH ₂ ) _0-4 SR ^o ; -SC(S)SR ^o ;-(CH ₂ ) _0-4 SC(O)R ^o ;-(CH ₂ ) _0-4 C(O)NR ^o ₂ ;-C(S)NR ^o ₂ ;-C (S)SR ^o ; -SC(S)SR ^o , -(CH ₂ ) _0-4 OC(O)NR ^o ₂ ; -C(O)N(OR ^o )R ^o ; -C(O)C( O)R ^o ;-C(O)CH ₂ C(O)R ^o ;-C(NOR ^o )R ^o ;-(CH ₂ ) _0-4 SSR ^o ;-(CH ₂ ) _0-4 S(O ) ₂ R ^o ;-(CH ₂ ) _0-4 S(O) ₂ OR ^o ;-(CH ₂ ) _0-4 OS(O) ₂ R ^o ;-S(O) ₂ NR ^o ₂ ;-(CH ₂ ) _0-4 S(O)R ^o ; -N(R ^o )S(O) ₂ NR ^o ₂ ;-N(R ^o )S(O) ₂ R ^o ;-N(OR ^o )R ^o ;-C(NH)NR ^o ₂ ;-P( O) ₂ R ^o ;-P(O)R ^o ₂ ;-OP(O)R ^o ₂ ;-OP(O)(OR ^o ) ₂ ; SiR ^o ₃ ;-(C _1-4 straight chain or branched chain Alkylene) ON(R ^o ) ₂ ; or -(C _1-4 linear or branched alkylene) C(O)ON(R ^o ) ₂ , wherein each R ^o can be substituted as defined below, And are independently hydrogen, C _1-6 aliphatic, -CH ₂ Ph, -O(CH ₂ ) _0-1 Ph, -CH _2- (5 to 6 membered heteroaryl ring) or have 0 to 4 independent A 5- to 6-membered saturated, partially unsaturated or aryl ring selected from the heteroatoms of nitrogen, oxygen or sulfur, or regardless of the above definition, two independently occurring R ^o and their intervening atoms form together with 0 to 4 independently The 3- to 12-membered saturated, partially unsaturated or aryl monocyclic or bicyclic ring of heteroatoms selected from nitrogen, oxygen or sulfur may be substituted as defined below.

Suitable monovalent substituents on R ^o (or a ring formed by two independently occurring R ^o and its inserted atom together) are independently halogen, -(CH ₂ ) _0-2 R ^˙ , -(halo R ^˙ ), -(CH ₂ ) _0-2 OH, -(CH ₂ ) _0-2 OR ^˙ , -(CH ₂ ) _0-2 CH(OR ^˙ ) ₂ ; -O(halo R ^˙ ), -CN, -N ₃ , -(CH ₂ ) _0-2 C(O)R ^˙ , -(CH ₂ ) _0-2 C(O)OH, -(CH ₂ ) _0-2 C(O)OR ^˙ , -(CH ₂ ) _0-2 SR ^˙ ,-(CH ₂ ) _0-2 SH, -(CH ₂ ) _0-2 NH ₂ , -(CH ₂ ) _0-2 NHR ^˙ , -(CH ₂ ) _0-2 NR ^˙ ₂ , -NO ₂ , -SiR ^˙ ₃ , -OSiR ^˙ ₃ , -C(O)SR ^˙ , -(C _1-4 linear or branched chain alkylene)C(O)OR ^˙ or -SSR ^˙ , where Each R ^˙ is unsubstituted or is only substituted by one or more halogens when adding "halo" in front, and is independently selected from C _1-4 aliphatic, -CH ₂ Ph, -O(CH ₂ ) _0-1 Ph or a 5- to 6-membered saturated, partially unsaturated or aryl ring with 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Suitable divalent substituents on the saturated carbon atom of R ^{o include =O and =S.}

Suitable divalent substituents on saturated carbon atoms of "optionally substituted" groups include the following: =O, =S, =NNR ^* ₂ , =NNHC(O)R ^* , =NNHC(O)OR ^* , = NNHS(O) ₂ R ^* , =NR ^* , =NOR ^* , -O(C(R ^* ₂ )) _2-3 O- or -S(C(R ^* ₂ )) _2-3 S-, each of which The independently occurring R ^* _{is selected from hydrogen, C 1-6} aliphatic which may be substituted as defined below, or saturated with 5 to 6 members having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, Partially unsaturated or aryl ring. Suitable divalent substituents bonded to the ortho-substitutable carbon of the "optionally substituted" group include: -O(CR ^* ₂ ) _2-3 O-, where each independently occurring R ^* is selected from hydrogen, _{A substituted C 1-6} aliphatic, or a 5- to 6-membered saturated, partially unsaturated or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, as defined below.

Suitable substituents on the aliphatic group of R ^{* include halogen, -R ˙} , -(halo R ^˙ ), -OH, -OR ^˙ , -O (halo R ^˙ ), -CN, -C(O )OH, -C(O)OR ^˙ , -NH ₂ , -NHR ^˙ , -NR ^˙ ₂ or -NO ₂ , where each R ^˙ is unsubstituted or is preceded by a "halo" with only one or Multiple halogen substitutions, independently of C _1-4 aliphatic, -CH ₂ Ph, -O(CH ₂ ) _0-1 Ph, or having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur 5- to 6-membered saturated, partially unsaturated or aryl ring.

Suitable substituents that can replace the nitrogen of the "optionally substituted" group include -R ^† , -NR ^† ₂ , -C(O)R ^† , -C(O)OR ^† , -C(O)C(O )R ^† , -C(O)CH ₂ C(O)R ^† , -S(O) ₂ R ^† , -S(O) ₂ NR ^† ₂ , -C(S)NR ^† ₂ , -C(NH )NR ^† ₂ or -N(R ^† )S(O) ₂ R ^† , wherein each R ^{† is} independently hydrogen, C _1-6 aliphatic substituted, unsubstituted -OPh or An unsubstituted 5- to 6-membered saturated, partially unsaturated or aryl ring with 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or regardless of the above definition, two independently occurring R ^† and its insertion The atoms together form a 3 to 12 membered saturated, partially unsaturated or aryl monocyclic or bicyclic ring with 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

Suitable substituents on the aliphatic group of R ^{† are independently halogen, -R ˙} , -(halo R ^˙ ), -OH, -OR ^˙ , -O (halo R ^˙ ), -CN, -C (O)OH, -C(O)OR ^˙ , -NH ₂ , -NHR ^˙ , -NR ^˙ ₂ or -NO ₂ , where each R ^˙ is unsubstituted or is only One or more halogen substituted, and independently C _1-4 aliphatic, -CH ₂ Ph, -O(CH ₂ ) _0-1 Ph, or having 0 to 4 heterocycles independently selected from nitrogen, oxygen or sulfur Five to six members of the atom are saturated, partially unsaturated or aryl rings.

As used herein, the term "pharmaceutically acceptable salts" means that they are suitable for contact with human and lower animal tissues without abnormal toxicity, irritation, allergic reactions, etc. under a reasonable range of medical judgments, and A salt that meets a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are amine groups and inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or organic acids (such as acetic acid, oxalic acid, maleic acid, tartaric acid). , Citric acid, succinic acid or malonic acid) or salts formed by using other methods used in the art (such as ion exchange). Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, besylate, benzoate, bisulfate, borate, butyrate, camphorate , Camphor sulfonate, citrate, cyclopentane propionate, bis gluconate, lauryl sulfate, ethane sulfonate, formate, fumarate, glucoheptonate, glycerophosphate Salt, gluconate, hemisulfate, heptanoate, caproate, hydroiodide, 2-hydroxy-ethane sulfonate, lactobionate, lactate, lauric acid, lauryl sulfate, Malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonic acid Salt, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate , Pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc.

Salts derived from suitable bases include alkali metal salts, alkaline earth metal salts, ammonium salts and N ⁺ (C _1-4 alkyl) ₄ salts. Representative alkali metal or alkaline earth metal salts include sodium salt, lithium salt, potassium salt, calcium salt, magnesium salt and the like. Where appropriate, other pharmaceutically acceptable salts include the use of counter ions (such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, low carbon number alkylsulfonate, and aryl). Sulfonate ion) formed by non-toxic ammonium salt, quaternary ammonium salt and amine cation.

Unless otherwise specified, the structure described herein is also intended to include all isomeric (e.g., enantiomers, diastereomers, and geometric (or conformational)) forms of the structure; for example, each asymmetric center R and S configuration, Z and E double bond isomers, and Z and E conformation isomers. Therefore, single stereochemical isomers, enantiomers, diastereomers, and geometric (or conformational) mixtures of the compounds of the present invention are all within the scope of the present invention. Unless otherwise specified, all tautomeric forms of the compounds of the present invention are within the scope of the present invention. In addition, unless otherwise stated, the structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, a compound having the structure of the present invention including the replacement of hydrogen with deuterium or tritium, or the ^{replacement of carbon with 13} C- or ¹⁴ C-concentrated carbon is within the scope of the present invention. These compounds can be used, for example, as analytical tools, as probes in biological analysis or as therapeutic agents of the present invention. In certain embodiments, the warhead portion R ^{1 of} the provided compound contains one or more deuterium atoms. In certain embodiments, ring B of the provided compound may be substituted with one or more deuterium atoms.

As used herein, the term "inhibitor" is defined as a compound that binds and/or inhibits TYK2 with a measurable affinity. In certain embodiments, the inhibitor is less than about 50 M, less than about [mu] M, less than about 500 nM, less than about 10OnM, less than about 10nM or less than about 1nM of IC ₅₀ and / or the binding constant.

The compounds of the invention can be tethered to a detectable moiety. It should be understood that these compounds can be used as imaging agents. The skilled artisan will understand that the detectable moiety can be attached to the provided compound via suitable substituents. As used herein, the term "suitable substituent" refers to a moiety that can be covalently attached to a detectable moiety. These moieties are well known to those skilled in the art, and include groups containing, for example, a carboxylate moiety, an amine moiety, a thiol moiety, or a hydroxyl moiety (to name a few). It should be understood that these moieties can be attached to the provided compound directly or via a tethering group, such as a divalent saturated or unsaturated hydrocarbon chain. In some embodiments, these parts may be attached via click chemistry. In some embodiments, these parts may be attached via 1,3-cycloaddition of azide and alkyne in the presence of a copper catalyst as appropriate. Methods using click chemistry are known in the art, and include them by Rostovtsev et al., Angew. Chem. Int. Ed. 2002, 41 , 2596-99 and Sun et al., Bioconjugate Chem., 2006, 17. , 52-57.

As used herein, the term "detectable part" can be used interchangeably with the term "label" and refers to any part that can be detected, for example, primary label and secondary label. Primary labels (such as radioisotopes (for example, tritium, ³² P, ³³ P, ³⁵ S or ¹⁴ C), mass labels and fluorescent labels) are signal generation reporter groups that can be detected without further modification. The detectable moiety also includes luminescent and phosphorescent groups.

The term "secondary label" as used herein refers to a part that requires the presence of a second intermediate to generate a detectable signal, such as biotin and various protein antigens. In the case of biotin, the second intermediate may include a streptavidin-enzyme conjugate. For antigen labels, the second intermediate may include an antibody-enzyme conjugate. Some fluorescent groups act as secondary labels because they transfer energy to another group during a non-radioactive fluorescent resonance energy transfer (FRET) process, and the second group generates a detection signal.

As used herein, the terms "fluorescent label", "fluorescent dye" and "fluorescent group" refer to the part that absorbs light energy with a limited excitation wavelength and emits light energy with different wavelengths. Screen cursor Examples include (but are not limited to): Alexa Fluor dyes (Alexa Fluor 350, Alexa Fluor 488, Alexa Fluor 532, Alexa Fluor 546, Alexa Fluor 568, Alexa Fluor 594, Alexa Fluor 633, Alexa Fluor 660 and Alexa Fluor 680) , AMCA, AMCA-S, BODIPY dyes (BODIPY FL, BODIPY R6G, BODIPY TMR, BODIPY TR, BODIPY 530/550, BODIPY 558/568, BODIPY 564/570, BODIPY 576/589, BODIPY 581/591, BODIPY 630/ 650, BODIPY 650/665), carboxyrhodamine 6G, carboxy-X-rhodamine (ROX), Cascade blue, Cascade yellow, coumarin 343, cyanine dyes (Cy3, Cy5, Cy3.5, Cy5.5) , Dansyl, Dapoxyl, dialkylamino coumarin, 4',5'-dichloro-2',7'-dimethoxy-luciferin, DM-NERF, eosin, Erythrosine, luciferin, FAM, hydroxycoumarin, IR dyes (IRD40, IRD 700, IRD 800), JOE, lissamine rhodamine B, Marina blue, methoxycoumarin, naphthofluorescence Vegetarian, Oregon Green 488, Oregon Green 500, Oregon Green 514, Pacific Blue, PyMPO, Pyrene, Rhodamine B, Rhodamine 6G, Rhodamine Green, Rhodamine Red, Rhodol Green, 2', 4', 5', 7 '-Tetra-bromo-fluorescein, tetramethyl-rhodamine (TMR), carboxytetramethylrhodamine (TAMRA), Texas Red, Texas Red-X.

As used herein, the term "mass label" refers to any part that can be uniquely detected by mass spectrometry (MS) detection technology by virtue of its mass. Examples of quality labels include electrophoretic release labels, such as N-[3-[4'-[(p-methoxytetrafluorobenzyl)oxy]phenyl]-3-methylglyceronyl (glyceronyl)] iso Pyridine carboxylic acid, 4'-[2,3,5,6-tetrafluoro-4-(pentafluorophenoxy)]methylacetophenone and its derivatives. The synthesis and utility of these quality labels are described in U.S. Patent Nos. 4,650,750, 4,709,016, 5,360,8191, 5,516,931, 5,602,273, 5,604,104, 5,610,020, and 5,650,270. Other examples of quality labels include (but are not limited to) nucleotides, dideoxynucleotides, oligonucleotides with different lengths and base compositions, oligopeptides, oligosaccharides, and other synthetics with different lengths and monomer compositions polymer. All kinds of organic molecules (neutral and charged) with suitable mass range (100 to 2000 Daltons) (biological Molecules or synthetic compounds) can also be used as quality labels.

The terms "measurable affinity" and "measurable inhibition" as used herein mean that the activity of TYK2 protein kinase is measured in samples containing the compound of the present invention or its composition and TYK2 protein kinase and samples containing TYK2 protein kinase, without the compound or The measurable change between equivalent samples in the presence of the composition.

3. Description of exemplary embodiments:

或其醫藥上可接受之鹽，其中：X及Y各自獨立地為=C(R⁶)-或=N-，限制條件為X及Y不同時為=C(R⁶)-；環A為苯基；具有1至4個獨立地選自氮、氧及硫之雜原子之5至6員雜芳基環；具有1至2個獨立地選自氮、氧及硫之雜原子之3至6員飽和或部分不飽和雜環環；4至6員飽和或部分不飽和碳環環；其中環A經m個R⁷實例取代；R¹及R^1’各自獨立地為氫、-R²、鹵素、-CN、-NO₂、-OR、-SR、-NR₂、-S(O)₂R、-S(O)₂NR₂、-S(O)R、-C(O)R、-C(O)OR、-C(O)NR₂、-C(O)N(R)OR、-OC(O)R、-OC(O)NR₂、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR₂或-N(R)S(O)₂R；或R¹及R^1’一起形成側氧基或者與其插入原子形成視情況經取代之具有0至2個獨立地選自氮、氧及硫之雜原子之3至7員螺式稠合環；各R²獨立地為選自以下之視情況經取代之基團：C_1-6脂族、苯基、具有1至2個獨立地選自氮、氧及硫之雜原子之4至7員飽和或部分 不飽和雜環環、以及具有1至4個獨立地選自氮、氧及硫之雜原子之5至6員雜芳基環；R³為選自以下之基團：C_1-6烷基、苯基、3至7員飽和或部分不飽和碳環環、具有1至2個獨立地選自氮、氧及硫之雜原子之3至7員飽和或部分不飽和雜環環、及具有1至4個獨立地選自氮、氧及硫之雜原子之5至6員雜芳基環；其中R³經n個R⁸實例取代；R⁴為氫或視情況經取代之C_1-6脂族；或R⁴及一個R⁷實例與其插入原子一起形成具有1至4個獨立地選自氮、氧及硫之雜原子之5至6員部分不飽和或芳族環；R⁵為具有1至2個獨立地選自氮、氧及硫之雜原子之8至10員飽和或部分不飽和雜環環；其中R⁵經p個R⁹實例取代；R⁶、R⁷、R⁸、R¹⁰及R¹¹之各實例獨立地為-R²、鹵素、-CN、-NO₂、-OR、-SR、-NR₂、-S(O)₂R、-S(O)₂NR₂、-S(O)R、-C(O)R、-C(O)OR、-C(O)NR₂、-C(O)N(R)OR、-OC(O)R、-OC(O)NR₂、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR₂或-N(R)S(O)₂R；R⁹之各實例獨立地為側氧基、C_1-6羥基脂族、-R²、鹵素、-CN、-NO₂、-OR、-SR、-NR₂、-S(O)₂R、-S(O)₂NR₂、-S(O)R、-C(O)R、-C(O)OR、-C(O)NR₂、-C(O)N(R)OR、-OC(O)R、-OC(O)NR₂、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR₂或-N(R)S(O)₂R；L¹為共價鍵或C_1-6二價飽和或不飽和直鏈或分支鏈烴鏈，其中該鏈之一或兩個亞甲基單元視情況且獨立地經-C(R¹⁰)₂-、-N(R)-、-N(R)C(O)-、-C(O)N(R)-、-N(R)S(O)₂-、-S(O)₂N(R)-、-O-、-C(O)-、-OC(O)-、-C(O)O-、-S-、-S(O)-或-S(O)₂-置換；或L¹及一個R⁷實例與其插入原子一起形成具有1至4個獨立地選自氮、氧及硫之雜原子之5至10員部分不飽和或芳族環；其中該環經q個R¹¹實例取代；且R⁵附接至由L¹及R⁷所形成環之任何位置； m為0至4；n為0至4；p為0至6；q為0至4；且各R獨立地為氫或選自以下之視情況經取代之基團：C_1-6脂族、苯基、具有1至2個獨立地選自氮、氧及硫之雜原子之4至7員飽和或部分不飽和雜環、以及具有1至4個獨立地選自氮、氧及硫之雜原子之5至6員雜芳基環；或相同氮上之兩個R與其插入原子一起形成除該氮以外具有0至3個獨立地選自氮、氧及硫之雜原子之4至7員飽和、部分不飽和或雜芳基環。 As mentioned above, in certain embodiments, the present invention provides a compound of formula I :

Or a pharmaceutically acceptable salt thereof, wherein: X and Y are each independently =C(R ⁶ )- or =N-, and the restriction is that X and Y are not at the same time =C(R ⁶ )-; ring A is Phenyl; a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; 3 to 3 to having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur 6-membered saturated or partially unsaturated heterocyclic ring; 4 to 6-membered saturated or partially unsaturated carbocyclic ring; wherein ring A is ^{substituted by m instances of R 7} ; R ¹ and R ^1'are each independently hydrogen, -R ² , Halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -C(O)R , -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O ) oR, -N (R) C (O) R, -N (R) C (O) NR 2 or -N (R) S (O) 2 R; or R ¹ and R ^{1 'together} form oxo Or form an optionally substituted 3- to 7-membered spiro fused ring with 0 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur with the inserted atom; each R ^{2 is} independently selected from the following optional Substituted groups: C _1-6 aliphatic, phenyl, 4 to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and having 1 Up to 4 5- to 6-membered heteroaryl rings independently selected from heteroatoms of nitrogen, oxygen and sulfur; R ³ is a group selected from: C _1-6 alkyl, phenyl, 3 to 7-membered saturated Or partially unsaturated carbocyclic ring, 3 to 7 member saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and having 1 to 4 independently selected from nitrogen 5 to 6-membered heteroaryl rings of heteroatoms of, oxygen and sulfur; wherein R ³ is substituted with n ^{instances of R 8} ; R ⁴ is hydrogen or optionally substituted C _1-6 aliphatic; or R ⁴ and one Examples of R ⁷ together with their intervening atoms form a 5- to 6-member partially unsaturated or aromatic ring with 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; R ⁵ is with 1 to 2 independently selected from The 8- to 10-membered saturated or partially unsaturated heterocyclic ring of nitrogen, oxygen and sulfur heteroatoms; wherein R ⁵ is substituted by p ^{examples of R 9} ; each example of ^{R 6} , R ⁷ , R ⁸ , R ¹⁰ and R ¹¹ Independently -R ² , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ₂ , -N (R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ₂ or -N(R)S(O) ₂ R; each instance of ^{R 9 is independent} Side oxygen Group, C _1-6 hydroxy aliphatic, -R ² , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC( O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ₂ or -N(R)S(O) ₂ R ; L ¹ is a covalent bond or a C _1-6 divalent saturated or unsaturated straight or branched hydrocarbon chain, wherein one or two methylene units of the chain optionally and independently undergoes -C(R ¹⁰ ) ₂ -, -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O) ₂ -, -S(O) ₂ N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O) _2- Substitution; or L ¹ and an ^{example of R 7} together with their intervening atoms form a 5- to 10-membered partially unsaturated or aromatic ring with 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein the ring passes through q An instance of R ^{11 is} substituted; and R ^{5 is} attached to ^{any position of the ring formed by L 1} and R ⁷ ; m is 0 to 4; n is 0 to 4; p is 0 to 6; q is 0 to 4; and Each R is independently hydrogen or an optionally substituted group selected from: C _1-6 aliphatic, phenyl, 4 to 7 having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur A saturated or partially unsaturated heterocyclic ring with a member and a 5- to 6-membered heteroaryl ring with 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or two Rs on the same nitrogen are formed together with their inserted atoms In addition to the nitrogen, a 4- to 7-membered saturated, partially unsaturated or heteroaryl ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

或其醫藥上可接受之鹽，其中：X及Y各自獨立地為=C(R⁶)-或=N-，限制條件為X及Y不同時為=C(R⁶)-；環A為苯基；具有1至4個獨立地選自氮、氧及硫之雜原子之5至6員雜芳基環；具有1至2個獨立地選自氮、氧及硫之雜原子之3至6員飽和或部分不飽和雜環環；4至6員飽和或部分不飽和碳環環；其中環A經m個R⁷實例取代；R¹及R^1’各自獨立地為氫、-R²、鹵素、-CN、-NO₂、-OR、-SR、-NR₂、-S(O)₂R、-S(O)₂NR₂、-S(O)R、-C(O)R、-C(O)OR、- C(O)NR₂、-C(O)N(R)OR、-OC(O)R、-OC(O)NR₂、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR₂或-N(R)S(O)₂R；或R¹及R^1’一起形成側氧基或者與其插入原子形成視情況經取代之具有0至2個獨立地選自氮、氧及硫之雜原子之3至7員螺式稠合環；各R²獨立地為選自以下之視情況經取代之基團：C_1-6脂族、苯基、具有1至2個獨立地選自氮、氧及硫之雜原子之4至7員飽和或部分不飽和雜環環、以及具有1至4個獨立地選自氮、氧及硫之雜原子之5至6員雜芳基環；R³為選自以下之基團：C_1-6烷基、苯基、3至7員飽和或部分不飽和碳環環、具有1至2個獨立地選自氮、氧及硫之雜原子之3至7員飽和或部分不飽和雜環環、及具有1至4個獨立地選自氮、氧及硫之雜原子之5至6員雜芳基環；其中R³經n個R⁸實例取代；R⁴為氫或視情況經取代之C_1-6脂族；或R⁴及一個R⁷實例與其插入原子一起形成具有1至4個獨立地選自氮、氧及硫之雜原子之5至6員部分不飽和或芳族環；R⁵為選自以下之基團：氫、鹵素、-CN、-NO₂、-OR、-SR、-NR₂、-S(O)₂R、-S(O)₂NR₂、-S(O)R、-C(O)R、-C(O)OR、-C(O)NR₂、-C(O)N(R)OR、-OC(O)R、-OC(O)NR₂、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR₂、-N(R)S(O)₂R、苯基、具有1至2個獨立地選自氮、氧及硫之雜原子之3至10員飽和或部分不飽和雜環環、及具有1至4個獨立地選自氮、氧及硫之雜原子之5至6員雜芳基環；其中R⁵經p個R⁹實例取代；R⁶、R⁷、R⁸、R¹⁰及R¹¹之各實例獨立地為-R²、鹵素、-CN、-NO₂、-OR、-SR、-NR₂、-S(O)₂R、-S(O)₂NR₂、-S(O)R、-C(O)R、-C(O)OR、-C(O)NR₂、-C(O)N(R)OR、-OC(O)R、-OC(O)NR₂、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR₂或-N(R)S(O)₂R； R⁹之各實例獨立地為側氧基、C_1-6羥基脂族、-R²、鹵素、-CN、-NO₂、-OR、-SR、-NR₂、-S(O)₂R、-S(O)₂NR₂、-S(O)R、-C(O)R、-C(O)OR、-C(O)NR₂、-C(O)N(R)OR、-OC(O)R、-OC(O)NR₂、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR₂或-N(R)S(O)₂R；L^1’為C_1-6二價飽和或不飽和直鏈或分支鏈烴鏈，其中該鏈之至少一個亞甲基單元經-C(R¹⁰)₂-置換；且該鏈之至少一個或兩個另外的亞甲基單元視情況且獨立地經-N(R)-、-N(R)C(O)-、-C(O)N(R)-、-N(R)S(O)₂-、-S(O)₂N(R)-、-O-、-C(O)-、-OC(O)-、-C(O)O-、-S-、-S(O)-或-S(O)₂-置換；或L^1’及一個R⁷實例與其插入原子一起形成具有1至4個獨立地選自氮、氧及硫之雜原子之5至10員部分不飽和或芳族環；其中該環經q個R¹¹實例取代；且R⁵附接至由L^1’及R⁷所形成環之任何位置；m為0至4；n為0至4；p為0至6；q為0至4；且各R獨立地為氫或選自以下之視情況經取代之基團：C_1-6脂族、苯基、具有1至2個獨立地選自氮、氧及硫之雜原子之4至7員飽和或部分不飽和雜環、以及具有1至4個獨立地選自氮、氧及硫之雜原子之5至6員雜芳基環；或相同氮上之兩個R與其插入原子一起形成除該氮以外具有0至3個獨立地選自氮、氧及硫之雜原子之4至7員飽和、部分不飽和或雜芳基環。 In certain embodiments, the present invention provides a compound of formula II :

Or a pharmaceutically acceptable salt thereof, wherein: X and Y are each independently =C(R ⁶ )- or =N-, and the restriction is that X and Y are not at the same time =C(R ⁶ )-; ring A is Phenyl; a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; 3 to 3 to having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur 6-membered saturated or partially unsaturated heterocyclic ring; 4 to 6-membered saturated or partially unsaturated carbocyclic ring; wherein ring A is ^{substituted by m instances of R 7} ; R ¹ and R ^1'are each independently hydrogen, -R ² , Halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -C(O)R , -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O ) oR, -N (R) C (O) R, -N (R) C (O) NR 2 or -N (R) S (O) 2 R; or R ¹ and R ^{1 'together} form oxo Or form an optionally substituted 3- to 7-membered spiro fused ring with 0 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur with the inserted atom; each R ^{2 is} independently selected from the following optional Substituted groups: C _1-6 aliphatic, phenyl, 4 to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and having 1 Up to 4 5- to 6-membered heteroaryl rings independently selected from heteroatoms of nitrogen, oxygen and sulfur; R ³ is a group selected from: C _1-6 alkyl, phenyl, 3 to 7-membered saturated Or partially unsaturated carbocyclic ring, 3 to 7 member saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and having 1 to 4 independently selected from nitrogen 5 to 6-membered heteroaryl rings of heteroatoms of, oxygen and sulfur; wherein R ³ is substituted with n ^{instances of R 8} ; R ⁴ is hydrogen or optionally substituted C _1-6 aliphatic; or R ⁴ and one Examples of R ⁷ together with their intervening atoms form a 5- to 6-member partially unsaturated or aromatic ring with 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; R ⁵ is a group selected from: hydrogen, Halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O) OR, -N(R)C(O)R, -N(R)C(O)NR ₂ , -N(R)S(O) ₂ R, phenyl, having 1 to 2 independently selected from nitrogen , 3 to 10 membered saturated or partially unsaturated heterocyclic rings of oxygen and sulfur heteroatoms, and 5 to 6 membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein R ⁵ is replaced by p ^{instances of R 9} ; R ⁶ , Each example of R ⁷ , R ⁸ , R ¹⁰ and R ^{11 is independently -R 2} , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S (O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -OC( O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ₂ or -N(R ) S(O) ₂ R; ^{Each example of R 9} is independently pendant oxy, C _1-6 hydroxy aliphatic, -R ² , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C( O)N(R)OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R) C(O)NR ₂ or -N(R)S(O) ₂ R; L ^1'is a C _1-6 divalent saturated or unsaturated linear or branched hydrocarbon chain, wherein at least one methylene group in the chain The unit is replaced by -C(R ¹⁰ ) ₂ -; and at least one or two additional methylene units of the chain are optionally and independently replaced by -N(R)-, -N(R)C(O)- , -C(O)N(R)-, -N(R)S(O) ₂ -, -S(O) ₂ N(R)-, -O-, -C(O)-, -OC( O)-, -C(O)O-, -S-, -S(O)- or -S(O) ₂ -replacement; or L ^1'and an ^{instance of R 7} together with its inserted atom are formed with 1 to 4 A 5- to 10-membered partially unsaturated or aromatic ring independently selected from heteroatoms of nitrogen, oxygen, and sulfur; wherein the ring is ^{substituted with q instances of R 11} ; and R ^{5 is} attached to L ^1′ and R ⁷ Any position of the formed ring; m is 0 to 4; n is 0 to 4; p is 0 to 6; q is 0 to 4; and each R is independently hydrogen or an optionally substituted group selected from the following : C _1-6 aliphatic, phenyl, 4 to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and having 1 to 4 independently selected A 5- to 6-membered heteroaryl ring from heteroatoms of nitrogen, oxygen and sulfur; or two Rs on the same nitrogen and their intervening atoms form together with 0 to 3 independently selected from nitrogen, oxygen and sulfur in addition to the nitrogen The 4 to 7-membered heteroatoms are saturated, partially unsaturated or heteroaryl rings.

或其醫藥上可接受之鹽，其中：X及Y各自獨立地為=C(R⁶)-或=N-，限制條件為X及Y不同時為=C(R⁶)-；環A為苯基；具有1至4個獨立地選自氮、氧及硫之雜原子之5至6員雜芳基環；具有1至2個獨立地選自氮、氧及硫之雜原子之3至6員飽和或部分不飽和雜環環；4至6員飽和或部分不飽和碳環環；其中環A經m個R⁷實例取代；R¹及R^1’各自獨立地為氫、-R²、鹵素、-CN、-NO₂、-OR、-SR、-NR₂、-S(O)₂R、-S(O)₂NR₂、-S(O)R、-C(O)R、-C(O)OR、-C(O)NR₂、-C(O)N(R)OR、-OC(O)R、-OC(O)NR₂、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR₂或-N(R)S(O)₂R；或R¹及R^1’一起形成側氧基或者與其插入原子形成視情況經取代之具有0至2個獨立地選自氮、氧及硫之雜原子之3至7員螺式稠合環；各R²獨立地為選自以下之視情況經取代之基團：C_1-6脂族、苯基、具有1至2個獨立地選自氮、氧及硫之雜原子之4至7員飽和或部分不飽和雜環環、以及具有1至4個獨立地選自氮、氧及硫之雜原子之5至6員雜芳基環；R³為選自以下之基團：C_1-6烷基、苯基、3至7員飽和或部分不飽和碳環環、具有1至2個獨立地選自氮、氧及硫之雜原子之3至7員飽和或部分不飽和雜環環、及具有1至4個獨立地選自氮、氧及硫之雜原子之5至6員雜芳基環；其中R³經n個R⁸實例取代；R^4’及一個R⁷實例與其插入原子一起形成具有1至4個獨立地選自 氮、氧及硫之雜原子之5至6員部分不飽和或芳族環；R⁵為選自以下之基團：鹵素、-CN、-NO₂、-OR、-SR、-NR₂、-S(O)₂R、-S(O)₂NR₂、-S(O)R、-C(O)R、-C(O)OR、-C(O)NR₂、-C(O)N(R)OR、-OC(O)R、-OC(O)NR₂、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR₂、-N(R)S(O)₂R、苯基、具有1至2個獨立地選自氮、氧及硫之雜原子之3至10員飽和或部分不飽和雜環環、及具有1至4個獨立地選自氮、氧及硫之雜原子之5至6員雜芳基環；其中R⁵經p個R⁹實例取代；R⁶、R⁷、R⁸、R¹⁰及R¹¹之各實例獨立地為-R²、鹵素、-CN、-NO₂、-OR、-SR、-NR₂、-S(O)₂R、-S(O)₂NR₂、-S(O)R、-C(O)R、-C(O)OR、-C(O)NR₂、-C(O)N(R)OR、-OC(O)R、-OC(O)NR₂、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR₂或-N(R)S(O)₂R；R⁹之各實例獨立地為側氧基、C_1-6羥基脂族、-R²、鹵素、-CN、-NO₂、-OR、-SR、-NR₂、-S(O)₂R、-S(O)₂NR₂、-S(O)R、-C(O)R、-C(O)OR、-C(O)NR₂、-C(O)N(R)OR、-OC(O)R、-OC(O)NR₂、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR₂或-N(R)S(O)₂R；L¹為共價鍵或C_1-6二價飽和或不飽和直鏈或分支鏈烴鏈，其中該鏈之一或兩個亞甲基單元視情況且獨立地經-C(R¹⁰)₂-、-N(R)-、-N(R)C(O)-、-C(O)N(R)-、-N(R)S(O)₂-、-S(O)₂N(R)-、-O-、-C(O)-、-OC(O)-、-C(O)O-、-S-、-S(O)-或-S(O)₂-置換；或L¹及一個R⁷實例與其插入原子一起形成具有1至4個獨立地選自氮、氧及硫之雜原子之5至10員部分不飽和或芳族環；其中該環經q個R¹¹實例取代；且R⁵附接至由L¹及R⁷所形成環之任何位置；L^2’為C_2-6二價飽和或不飽和直鏈或分支鏈烴鏈，其中至少一個亞甲基單元經-N(R⁴)-置換；且該鏈之至少一個或兩個另外的亞甲基單元視情況且獨立地經-C(R¹⁰)₂-、-N(R)-、-N(R)C(O)-、-C(O)N(R)-、- N(R)S(O)₂-、-S(O)₂N(R)-、-O-、-C(O)-、-OC(O)-、-C(O)O-、-S-、-S(O)-或-S(O)₂-置換；或L²為-N(R^4’)-；m為0至4；n為0至4；p為0至6；q為0至4；且各R獨立地為氫或選自以下之視情況經取代之基團：C_1-6脂族、苯基、具有1至2個獨立地選自氮、氧及硫之雜原子之4至7員飽和或部分不飽和雜環、以及具有1至4個獨立地選自氮、氧及硫之雜原子之5至6員雜芳基環；或相同氮上之兩個R與其插入原子一起形成除該氮以外具有0至3個獨立地選自氮、氧及硫之雜原子之4至7員飽和、部分不飽和或雜芳基環。 In certain embodiments, the present invention provides a compound of formula III' :

Or a pharmaceutically acceptable salt thereof, wherein: X and Y are each independently =C(R ⁶ )- or =N-, and the restriction is that X and Y are not at the same time =C(R ⁶ )-; ring A is Phenyl; a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; 3 to 3 to having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur 6-membered saturated or partially unsaturated heterocyclic ring; 4 to 6-membered saturated or partially unsaturated carbocyclic ring; wherein ring A is ^{substituted by m instances of R 7} ; R ¹ and R ^1'are each independently hydrogen, -R ² , Halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -C(O)R , -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O ) oR, -N (R) C (O) R, -N (R) C (O) NR 2 or -N (R) S (O) 2 R; or R ¹ and R ^{1 'together} form oxo Or form an optionally substituted 3- to 7-membered spiro fused ring with 0 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur with the inserted atom; each R ^{2 is} independently selected from the following optional Substituted groups: C _1-6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and having 1 Up to 4 5- to 6-membered heteroaryl rings independently selected from heteroatoms of nitrogen, oxygen and sulfur; R ³ is a group selected from: C _1-6 alkyl, phenyl, 3 to 7-membered saturated Or partially unsaturated carbocyclic ring, 3 to 7 member saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and having 1 to 4 independently selected from nitrogen A 5- to 6-membered heteroaryl ring of heteroatoms of, oxygen and sulfur; wherein R ³ is substituted by n ^{instances of R 8} ; R ^4'and one ^{instance of R 7} are formed together with the intervening atoms and have 1 to 4 independently selected from The 5- to 6-membered partially unsaturated or aromatic ring of nitrogen, oxygen and sulfur heteroatoms; R ⁵ is a group selected from the group consisting of halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O) )N(R)OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C (O)NR ₂ , -N(R)S(O) ₂ R, phenyl, 3 to 10 member saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur Ring, and 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein R ⁵ is substituted with p ^{instances of R 9} ; R ⁶ , R ⁷ , R ⁸ , Each instance of R ¹⁰ and R ^{11 is unique} The site is -R ² , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R,- C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ₂ , -N( R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ₂ or -N(R)S(O) ₂ R; each instance of ^{R 9 is independently} For pendant oxy, C _1-6 hydroxy aliphatic, -R ² , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ₂ or -N(R)S(O ) ₂ R; L ¹ is a covalent bond or a C _1-6 divalent saturated or unsaturated straight or branched hydrocarbon chain, wherein one or two methylene units of the chain are optionally and independently via -C( R ¹⁰ ) ₂ -, -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O) ₂ -, -S( O) ₂ N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O ) ₂ -substitution; or L ¹ and one R ⁷ instance together with the inserted atoms form a 5- to 10-membered partially unsaturated or aromatic ring with 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein The ring is ^{substituted with q instances of R 11} ; and R ^{5 is} attached to any position of the ring formed ^{by L 1} and R ^{7 ; L 2'is} a C _2-6 divalent saturated or unsaturated straight or branched hydrocarbon chain, Wherein at least one methylene unit is ^{replaced by -N(R 4} )-; and at least one or two other methylene units of the chain are optionally and independently replaced by -C(R ¹⁰ ) ₂ -, -N( R)-, -N(R)C(O)-, -C(O)N(R)-,-N(R)S(O) ₂ -, -S(O) ₂ N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O) ₂ -replacement; or L ² is -N(R ^4' )-; m is 0 to 4; n is 0 to 4; p is 0 to 6; q is 0 to 4; and each R is independently hydrogen or optionally substituted Group: C _1-6 aliphatic, phenyl, 4 to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and having 1 to 4 independent heteroatoms 5- to 6-membered heteroaryl ring selected from heteroatoms of nitrogen, oxygen and sulfur; or two on the same nitrogen Each R and its intervening atom together form a 4- to 7-membered saturated, partially unsaturated or heteroaryl ring with 0 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur in addition to the nitrogen.

或其醫藥上可接受之鹽，其中X、Y、環A、R¹、R^1’、L¹、R³、R⁴、R^4’、R⁵各自係如上文所定義及如本文實施例中所述，單獨地及組合地。 In certain embodiments, the present invention provides a compound of formula III' , wherein L ² is -N(R ^4' )-, thereby forming a compound of formula III :

Or a pharmaceutically acceptable salt thereof, wherein X, Y, ring A, R ¹ , R ^{1 '} , L ¹ , R ³ , R ⁴ , R ^4' , R ⁵ are each as defined above and as in the examples herein As described in, individually and in combination.

或其醫藥上可接受之鹽，其中：X及Y各自獨立地為=C(R⁶)-或=N-，限制條件為X及Y不同時為=C(R⁶)-；環A為苯基；具有1至4個獨立地選自氮、氧及硫之雜原子之5至6員雜芳基環；具有1至2個獨立地選自氮、氧及硫之雜原子之3至6員飽和或部分不飽和雜環環；4至6員飽和或部分不飽和碳環環；其中環A經m個R⁷實例取代；各R²獨立地為選自以下之視情況經取代之基團：C_1-6脂族、苯基、具有1至2個獨立地選自氮、氧及硫之雜原子之4至7員飽和或部分不飽和雜環環、以及具有1至4個獨立地選自氮、氧及硫之雜原子之5至6員雜芳基環；R³為選自以下之基團：C_1-6烷基、苯基、3至7員飽和或部分不飽和碳環環、具有1至2個獨立地選自氮、氧及硫之雜原子之3至7員飽和或部分不飽和雜環環、及具有1至4個獨立地選自氮、氧及硫之雜原子之5至6員雜芳基環；其中R³經n個R⁸實例取代；R⁴為氫或視情況經取代之C_1-6脂族；或R⁴及一個R⁷實例與其插入原子一起形成具有1至4個獨立地選自氮、氧及硫之雜原子之5至6員部分不飽和或芳族環；R⁵為選自以下之基團：鹵素、-CN、-NO₂、-OR、-SR、-NR₂、-S(O)₂R、-S(O)₂NR₂、-S(O)R、-C(O)R、-C(O)OR、-C(O)NR₂、-C(O)N(R)OR、-OC(O)R、-OC(O)NR₂、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR₂、-N(R)S(O)₂R、苯基、具有1至2個獨立地選自氮、氧 及硫之雜原子之3至10員飽和或部分不飽和雜環環、及具有1至4個獨立地選自氮、氧及硫之雜原子之5至6員雜芳基環；其中R⁵經p個R⁹實例取代；R⁶、R⁷、R⁸、R¹⁰及R¹¹之各實例獨立地為-R²、鹵素、-CN、-NO₂、-OR、-SR、-NR₂、-S(O)₂R、-S(O)₂NR₂、-S(O)R、-C(O)R、-C(O)OR、-C(O)NR₂、-C(O)N(R)OR、-OC(O)R、-OC(O)NR₂、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR₂或-N(R)S(O)₂R；R⁹之各實例獨立地為側氧基、C_1-6羥基脂族、-R²、鹵素、-CN、-NO₂、-OR、-SR、-NR₂、-S(O)₂R、-S(O)₂NR₂、-S(O)R、-C(O)R、-C(O)OR、-C(O)NR₂、-C(O)N(R)OR、-OC(O)R、-OC(O)NR₂、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR₂或-N(R)S(O)₂R；L¹為共價鍵或C_1-6二價飽和或不飽和直鏈或分支鏈烴鏈，其中該鏈之一或兩個亞甲基單元視情況且獨立地經-C(R¹⁰)₂-、-N(R)-、-N(R)C(O)-、-C(O)N(R)-、-N(R)S(O)₂-、-S(O)₂N(R)-、-O-、-C(O)-、-OC(O)-、-C(O)O-、-S-、-S(O)-或-S(O)₂-置換；或L¹及一個R⁷實例與其插入原子一起形成具有1至4個獨立地選自氮、氧及硫之雜原子之5至10員部分不飽和或芳族環；其中該環經q個R¹¹實例取代；且R⁵附接至由L¹及R⁷所形成環之任何位置；m為0至4；n為0至4；p為0至6；q為0至4；且各R獨立地為氫或選自以下之視情況經取代之基團：C_1-6脂族、苯基、具有1至2個獨立地選自氮、氧及硫之雜原子之4至7員飽和或部分不飽和雜環、以及具有1至4個獨立地選自氮、氧及硫之雜原子之5至6員雜芳基環；或 相同氮上之兩個R與其插入原子一起形成除該氮以外具有0至3個獨立地選自氮、氧及硫之雜原子之4至7員飽和、部分不飽和或雜芳基環。 In certain embodiments, the present invention provides a compound of formula IV :

Or a pharmaceutically acceptable salt thereof, wherein: X and Y are each independently =C(R ⁶ )- or =N-, and the restriction is that X and Y are not at the same time =C(R ⁶ )-; ring A is Phenyl; a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; 3 to 3 to having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur 6-membered saturated or partially unsaturated heterocyclic ring; 4 to 6-membered saturated or partially unsaturated carbocyclic ring; wherein ring A is ^{substituted with m instances of R 7} ; each R ^{2 is} independently selected from the following optionally substituted Group: C _1-6 aliphatic, phenyl, 4 to 7 member saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and having 1 to 4 A 5- to 6-membered heteroaryl ring independently selected from heteroatoms of nitrogen, oxygen and sulfur; R ³ is a group selected from: C _1-6 alkyl, phenyl, 3 to 7-membered saturated or partially non- Saturated carbocyclic ring, 3 to 7 member saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and having 1 to 4 independently selected from nitrogen, oxygen and 5- to 6-membered heteroaryl ring of sulfur heteroatoms; wherein R ³ is substituted with n ^{instances of R 8} ; R ⁴ is hydrogen or optionally substituted C _1-6 aliphatic; or R ⁴ and one R ⁷ instance Together with its intervening atoms, it forms a 5- to 6-member partially unsaturated or aromatic ring with 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; R ⁵ is a group selected from the group consisting of halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O) OR, -C(O)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N( R)C(O)R, -N(R)C(O)NR ₂ , -N(R)S(O) ₂ R, phenyl, having 1 to 2 independently selected from nitrogen, oxygen and sulfur 3 to 10 membered saturated or partially unsaturated heterocyclic ring of heteroatoms, and 5 to 6 membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein R ^{5 is} through p R ⁹ instance substitution; each instance of R ⁶ , R ⁷ , R ⁸ , R ¹⁰ and R ¹¹ is independently -R ² , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S (O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N (R)OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O )NR ₂ or -N(R)S(O) ₂ R; ^{each example of R 9} is independently pendant oxy, C _1-6 hydroxy aliphatic, -R ² , halogen, -CN, -NO ₂ ,- OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C (O)N(R)OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R )C(O)NR ₂ or -N(R)S(O) ₂ R; L ¹ is a covalent bond or a C _1-6 divalent saturated or unsaturated straight or branched hydrocarbon chain, one of which Or two methylene units as appropriate and independently through -C(R ¹⁰ ) ₂ -, -N(R)-, -N(R)C(O)-, -C(O)N(R)- , -N(R)S(O) ₂ -, -S(O) ₂ N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O- , -S-, -S(O)- or -S(O) ₂ -substitution; or L ¹ and an ^{example of R 7} together with its inserted atom form a heterocycle having 1 to 4 independently selected from nitrogen, oxygen and sulfur A 5- to 10-membered partially unsaturated or aromatic ring of atoms; wherein the ring is ^{substituted with q instances of R 11} ; and R ^{5 is} attached to ^{any position of the ring formed by L 1} and R ⁷ ; m is 0 to 4; n is 0 to 4; p is 0 to 6; q is 0 to 4; and each R is independently hydrogen or an optionally substituted group selected from the following: C _1-6 aliphatic, phenyl, having 1 Up to 2 saturated or partially unsaturated heterocyclic rings with 4 to 7 members independently selected from nitrogen, oxygen and sulfur, and 5 to 6 with 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur Member heteroaryl ring; or two Rs on the same nitrogen and their inserted atoms together form 4 to 7 members with 0 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur in addition to the nitrogen, saturated, partially unsaturated Or heteroaryl ring.

Generally as defined above, X and Y are each independently =C(R ⁶ )- or =N-, and the restriction is that X and Y are not at the same time =C(R ⁶ )-. In some embodiments, X and Y are both =N-. In some embodiments, X is =N-, and Y is =C(R ⁶ )-. In some embodiments, X is =C(R ⁶ )-, and Y is =N-.

In some embodiments, X and Y are each independently =C(R ⁶ )-, =N-, or =N ⁺ (→O ^- )-, and the restriction condition is that X and Y are not at the same time =C(R ⁶ ) -. In some embodiments, X is =C(R ⁶ )-, and Y is =N ⁺ (→O ^- )-.

Generally as described above, ring A is a phenyl group; a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or 1 to 2 independently selected from The 3 to 6-membered saturated or partially unsaturated heterocyclic ring of nitrogen, oxygen and sulfur heteroatoms; wherein ring A is substituted ^{with m instances of R 7.}

In some embodiments, ring A is phenyl. In some embodiments, Ring A is a 5- to 6-membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Ring A is a 5-membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is a 6-membered heteroaryl with 1 to 4 nitrogens. In some embodiments, Ring A is pyridyl. In some embodiments, Ring A is pyrazolyl.

Those of ordinary skill will understand that when ring A is a 5- to 6-membered heteroaryl ring, multiple regioisomers can exist. Unless otherwise stated, it is intended to include all regioisomers. In some embodiments, Ring A is 2-pyridyl. In some embodiments, Ring A is 3-pyridyl. In some embodiments, Ring A is 3-pyrazolyl. In some embodiments, Ring A is 4-pyrazolyl.

Likewise, when ring A is a phenyl group, there may be multiple attachment points. In some embodiments, when ring A is phenyl, L ¹ is the para position to the point of attachment to the rest of the molecule. In some embodiments, L ¹ is the position between the attachment points to the rest of the molecule. In some embodiments, L ¹ is adjacent to the attachment point to the remainder of the molecule. In some embodiments, when ring A is phenyl, and -L ¹ R ⁵ together are C _1-6 aliphatic, the -L ¹ R ⁵ group is para to the point of attachment to the rest of the molecule.

Generally as defined above, the n groups of formula I are 0-4. In some embodiments, n is zero. In some embodiments, n is 1 to 4. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

Generally as defined above, R ¹ and R ^1'are each independently hydrogen, -R ² , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR,- OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ₂ or -N (R)S(O) ₂ R; or R ¹ and R ^1'together with their intervening atoms form an optionally substituted 4 to 7 membered spiro with 0 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur式 fused ring.

In certain embodiments, R ¹ and R ^1'are each hydrogen. In some embodiments, R ¹ and R ^1'are each independently -R ² , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S( O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -OC(O )R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ₂ or -N(R) S(O) ₂ R. In certain embodiments, R ¹ and R ^1'are each methyl. In some embodiments, one of R ¹ and R ^1′ is methyl, and the other is hydrogen. In some embodiments, R ¹ and R ^{1 ′} together with their intervening atoms form an optionally substituted 3 to 7 membered spiro fused ring having 0 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R ¹ and R ^{1 ′} together with their intervening atoms form an optionally substituted 3- to 7-membered spiro fused carbocyclic ring. In some embodiments, R ¹ and R ^{1 ′} together with their intervening atoms form an optionally substituted spirocyclopropyl ring. In some embodiments, R ¹ and R ^1'together with their intervening atoms form an optionally substituted 3 to 7 membered spiro fused heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur ring.

Generally as defined above, R ³ is a group selected from: C _1-6 alkyl, phenyl, 3 to 7-membered saturated or partially unsaturated carbocyclic ring, with 1 to 2 nitrogen independently selected from , 3 to 7 membered saturated or partially unsaturated heterocyclic rings of oxygen and sulfur heteroatoms, and 5 to 6 membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein R ³ is substituted with n ^{instances of R 8.}

In some embodiments, R ³ is a group selected from: a phenyl group, a 3 to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, And a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

In some embodiments, R ³ is phenyl. In some embodiments, when X is =N-, R ³ is phenyl.

In some embodiments, R ³ is a 3 to 7 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R ³ is a 3 to 7 membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R ³ is a 5- to 6-membered saturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R ³ is pyrrolidinyl. In some embodiments, R ³ is piperidinyl.

In some embodiments, R ³ is a 5 to 6 membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R ³ is pyridyl. In some embodiments, R ³ is a C _3-6 saturated or partially unsaturated carbocyclic ring. Exemplary R ³ groups include those described in their Table 1.

Generally as defined above, R ⁴ is hydrogen or optionally substituted C _1-6 aliphatic. In some embodiments, R ⁴ is hydrogen. In some embodiments, R ^A1 is optionally substituted C _1-6 aliphatic. In some embodiments, R ⁴ is an unsubstituted C _1-6 aliphatic. In some embodiments, R ⁴ is optionally substituted C _1-6 alkyl. In some embodiments, R ⁴ is optionally substituted C _3-6 cycloalkyl.

Generally as defined above, L ¹ is a covalent bond or a C _1-6 divalent saturated or unsaturated straight or branched hydrocarbon chain, wherein one or two methylene units of the chain are optionally and independently via- N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O) ₂ -, -S(O) ₂ N(R) -, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O) ₂ -replacement; or L ¹ and one R ⁷ instance together with its intervening atoms form a 5- to 6-membered partially unsaturated or aromatic ring with 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein the ring has q R ¹¹ instances Substitute; and R ^{5 is} attached to any position of the ring formed ^{by L 1} and R ^7.

In some embodiments, L ¹ is a covalent bond or a C _1-6 divalent saturated or unsaturated straight or branched hydrocarbon chain, wherein one or two methylene units of the chain are optionally and independently via- N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O) ₂ -, -S(O) ₂ N(R) -, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O) ₂ -replacement.

In some embodiments, L ¹ and one R ⁷ instance together with their intervening atoms form a 5- to 6-membered partially unsaturated or aromatic ring with 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the The ring is ^{substituted with q instances of R 11} ; and R ^{5 is} attached to any position of the ring formed ^{by L 1} and R ^7.

In some embodiments, when L ¹ is a covalent bond, R ^{5 is} not an unsubstituted alkyl group. In some embodiments, L ¹ is a covalent bond. In other embodiments, L ¹ is a C _1-6 divalent hydrocarbon chain, wherein one or two methylene units of the chain are optionally and independently passed through -N(R)-, -N(R)C( O)-, -C(O)N(R)-, -N(R)S(O) ₂ -, -S(O) ₂ N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O) ₂ -replacement. In some embodiments, L ¹ is a C _2-6 divalent branched hydrocarbon chain. In some embodiments, L ¹ is a C _3-6 divalent branched alkylene chain.

In some embodiments, L ¹ is a C ₂ divalent hydrocarbon chain, wherein one methylene unit of the chain is replaced by -C(O)-. In some embodiments, L ¹ is -CH ₂ C(O)- (wherein the carbonyl group is ^{adjacent to R 5} ). In some embodiments, L ¹ is -C(O)-. In some embodiments, L ¹ is a covalent bond or -C(O)-. Exemplary L ¹ groups include those described in their Table 1.

In some embodiments, L ¹ is a covalent bond or a C _1-6 divalent saturated or unsaturated straight or branched hydrocarbon chain, wherein one or two methylene units of the chain are optionally and independently via- C(R ¹⁰ ) ₂ -, -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O) ₂ -,- S(O) ₂ N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S (O) ₂ -substitution; or L ¹ and an ^{example of R 7} together with its intervening atoms form a 5 to 10 member partially unsaturated or aromatic with 1 to 4 heteroatoms independently selected from nitrogen, oxygen, sulfur and boron Ring; wherein the ring is ^{substituted with q instances of R 11} ; and R ^{5 is} attached to any position of the ring formed ^{by L 1} and R ^7. In some embodiments, L ¹ and one R ⁷ instance together with their intervening atoms form a 5 to 10 membered partially unsaturated or aromatic ring with 1 to 4 heteroatoms independently selected from nitrogen, oxygen, sulfur, and boron; Wherein the ring is ^{substituted with q instances of R 11} ; and R ^{5 is} attached to any position of the ring formed ^{by L 1} and R ^7.

Generally as defined above, L ^1'is a C _1-6 divalent saturated or unsaturated straight or branched hydrocarbon chain, wherein at least one methylene unit of the chain is replaced by -C(R ¹⁰ ) ₂ -, and One or two other methylene units of the chain are optionally and independently passed through -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N( R)S(O) ₂ -, -S(O) ₂ N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S- , -S(O)- or -S(O) ₂ -substitution; or L ^1'and an ^{instance of R 7} together with the inserted atom form 5 of 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur To a 10-membered partially unsaturated or aromatic ring; wherein the ring is ^{substituted with q instances of R 11} ; and R ^{5 is} attached to any position of the ring formed ^{by L 1′} and R ^7.

In some embodiments, L ^{1 'is} -C (R ¹⁰⁾ ₂ -. In some embodiments, L ^1′ and one R ⁷ instance together with their intervening atoms form a 5- to 10-membered partially unsaturated or aromatic ring with 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein This ring is ^{substituted with q instances of R 11} ; and R ^{5 is} attached to any position of the ring formed ^{by L 1′} and R ^7. In some embodiments, L ^1′ and one R ⁷ instance together with their intervening atoms form a 5- to 6-membered partially unsaturated or aromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein This ring is ^{substituted with q instances of R 11} ; and R ^{5 is} attached to any position of the ring formed ^{by L 1′} and R ^7. In some embodiments, L ^1'and one R ⁷ instance together with their intervening atoms form a 7 to 10 membered partially unsaturated or aromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein This ring is ^{substituted with q instances of R 11} ; and R ^{5 is} attached to any position of the ring formed ^{by L 1′} and R ^7. Exemplary L ^{1 'groups} are described in Table 1.

In some embodiments, L ^1'is a C _1-6 divalent saturated or unsaturated straight or branched hydrocarbon chain, wherein at least one methylene unit of the chain is replaced by -C(R ¹⁰ ) ₂ -, and One or two other methylene units of the chain are optionally and independently passed through -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N( R)S(O) ₂ -, -S(O) ₂ N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S- , -S(O)- or -S(O) ₂ -substitution; or L ^1'and an ^{example of R 7} together with the inserted atom form 1 to 4 heteroatoms independently selected from nitrogen, oxygen, sulfur and boron Wherein the ring is ^{substituted with q instances of R 11} ; and R ^{5 is} attached to any position of the ring formed ^{by L 1′} and R ^7. In some embodiments, L ^1'and an ^{instance of R 7} together with their intervening atoms form a 5 to 10 membered partially unsaturated or aromatic ring with 1 to 4 heteroatoms independently selected from nitrogen, oxygen, sulfur, and boron ; Wherein the ring is ^{substituted with q instances of R 11} ; and R ^{5 is} attached to any position of the ring formed ^{by L 1′} and R ^7.

Generally as defined above, R ⁵ is a group selected from the group consisting of halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ₂ , -N(R)S(O ) ₂ R, phenyl, 3 to 7 member saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and having 1 to 4 independently selected from nitrogen, A 5- to 6-membered heteroaryl ring of oxygen and sulfur heteroatoms; wherein R ⁵ is substituted with p ^{instances of R 9.}

In some embodiments, R ^{5 is} selected from -OR, -NR ₂ and a 3 to 10 membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R ^{5 is} selected from -OH, -OEt, -NH ₂ , NHEt, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholine Group, oxabutanyl, tetrahydrothiopiperanyl and tetrahydrofuranyl. In some embodiments, R ⁵ is -OR. In some embodiments, R ⁵ is -NR ₂ . In some embodiments, R ⁵ is -NHEt or -NH i Pr. Exemplary R ⁵ groups include those in Table 1 their.

In some embodiments, R ⁵ is a 4 to 10 membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R ⁵ is a 4-membered saturated heterocyclic ring with 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, R ⁵ is a 5-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R ⁵ is a 6-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R ⁵ is a 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R ⁵ is an 8-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R ⁵ is a 9-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R ⁵ is a 10-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R ⁵ is an 8-membered saturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R ⁵ is a 9-membered saturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R ⁵ is a 10-membered saturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R ⁵ is a 7 to 10 membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R ⁵ is a 7 to 10 membered saturated or partially unsaturated fused bicyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, R ⁵ is a group selected from the group consisting of halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -OC(O)R,- OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ₂ , -N(R)S(O) ₂ R, phenyl, 3 to 14-membered saturated or partially unsaturated heterocyclic rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and having 1 to 4 independently selected from nitrogen, oxygen And a 5- to 6-membered heteroaryl ring of sulfur heteroatoms; wherein R ⁵ is substituted with p ^{instances of R 9.} In some embodiments, R ⁵ is a group selected from the group consisting of 3 to 14-membered saturated or partially unsaturated heterocyclic rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and having 1 Up to 4 5- to 6-membered heteroaryl rings independently selected from heteroatoms of nitrogen, oxygen and sulfur. In some embodiments, R ⁵ is a 3 to 14 membered saturated or partially unsaturated heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R ⁵ is a group selected from: a 10- to 14-membered saturated or partially unsaturated heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R ⁵ is a group selected from: a 10- to 14-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R ⁵ is a group selected from: a 10- to 14-membered saturated or partially unsaturated tricyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R ⁵ is a group selected from: a 10- to 14-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R ⁵ is a group selected from: a 10- to 14-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R ⁵ is a group selected from: a 10- to 14-membered saturated or partially unsaturated tricyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, R ^{5 '8} to 10 membered saturated or partially unsaturated heterocycle bridged bicyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur atoms of.

Substantially as hereinbefore defined, R ^{5 'with} 1 to 2 substituents independently selected from nitrogen, 8-10 saturated or partially unsaturated heterocyclic ring heteroatoms of oxygen and sulfur atoms; wherein p number of R ⁵ through R ⁹ Instance replacement. In some embodiments, R ^{5 'with} 1 to 2 substituents independently selected from nitrogen, oxygen and sulfur 8 hetero atoms of a saturated or partially unsaturated heterocyclic ring. In some embodiments, R ^{5 'with} 1 to 2 substituents independently selected from nitrogen, oxygen and sulfur and 9 of the hetero atom a saturated or partially unsaturated heterocyclic ring. In some embodiments, R ^{5 'with} 1 to 2 substituents independently selected from nitrogen, oxygen and sulfur 10 hetero atoms of a saturated or partially unsaturated heterocyclic ring. In some embodiments, R ^{5 'with} 1 to 2 substituents independently selected from nitrogen, oxygen and sulfur 8 hetero atoms of the heterocyclic saturated ring. In some embodiments, R ^{5 'with} 1 to 2 substituents independently selected from nitrogen, oxygen and sulfur 9 hetero atoms of the heterocyclic saturated ring. In some embodiments, R ^{5 '10} having one to two heteroatoms independently selected from nitrogen, oxygen and sulfur atoms of the heterocyclic saturated ring. In some embodiments, R ^{5 'with} 1 to 2 substituents independently selected from 8-10 saturated or partially unsaturated spiro ring hetero atoms nitrogen, oxygen and sulfur, the heterocyclic ring. In some embodiments, R ^5′ is an 8- to 10-membered saturated or partially unsaturated fused bicyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R ^{5 '8} to 10 membered saturated or partially unsaturated heterocycle bridged bicyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur atoms of.

In some embodiments, R ^{5 'having} 1 to 4 heteroatoms independently selected from nitrogen, 8-14 saturated or partially unsaturated heterocyclic ring heteroatoms of oxygen and sulfur atoms; Example ⁹ wherein R ⁵ through R & p replace. In some embodiments, R ^{5 'having} 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur 8 hetero atoms of to 12 membered saturated or partially unsaturated heterocyclic ring. In some embodiments, R ^{5 'having} 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur and 10 to 14 atoms of the hetero-membered saturated or partially unsaturated heterocyclic ring. In some embodiments, R ^{5 'with} 1 to 2 substituents independently selected from nitrogen, oxygen and sulfur and 8-14 hetero atoms of membered saturated or partially unsaturated heterocyclic ring. In some embodiments, R ^{5 'a} saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 8-14 heteroatoms independently selected from nitrogen, oxygen and sulfur of the. In some embodiments, R ^{5 'having} 1-4 8-14 heteroatoms independently selected from nitrogen, oxygen and sulfur of the saturated or partially unsaturated tricyclic heterocyclic ring.

Generally as defined above, each instance of ^{R 6 is independently -R 2} , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O ) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -OC(O) R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ₂ or -N(R)S (O) ₂ R. In some embodiments, R ⁶ is halogen or -CN. In some embodiments, R ⁶ is halogen. In some embodiments, R ⁶ is fluorine. In some embodiments, R ⁶ is -CN.

In some embodiments, R ⁶ is hydrogen, -R ² , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC (O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ₂ or -N(R)S(O) ₂ R. In some embodiments, R ⁶ is hydrogen. In some embodiments, R ⁶ is halogen or -CN. In some embodiments, R ⁶ is halogen. In some embodiments, R ⁶ is fluorine. In some embodiments, R ⁶ is -CN.

Generally as defined above, examples of ^{R 7 are -R 2} , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ₂ or -N(R)S(O ) ₂ R.

In some embodiments, R ⁷ is pendant oxy, -R ² , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ₂ or -N(R)S(O ) ₂ R.

Generally as defined above, each instance of ^{R 8 is independently -R 2} , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O ) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -OC(O) R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ₂ or -N(R)S (O) ₂ R. In some embodiments, R ⁸ is halogen. In some embodiments, R ⁸ is fluorine. In some embodiments, R ⁸ is chlorine. In some embodiments, R ⁸ is optionally substituted C _1-6 aliphatic. In some embodiments, R ⁸ is C _1-6 alkyl. In some embodiments, R ⁸ is methyl. In some embodiments, R ⁸ is an alkyl group substituted with one or more halogens. In some embodiments, R ⁸ is CF ₃ . In some embodiments, each R ⁸ is halogen. In some embodiments, each R ⁸ is fluorine, chlorine, methyl, or CF ₃ .

In some embodiments, R ⁸ is pendant oxy, -R ² , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ₂ or -N(R)S(O ) ₂ R.

The skilled person will understand ^{that the R 8} substituent on the saturated carbon of ^{R 3} forms an opposing center. In some embodiments, the palmar center is in the (R) configuration. In other embodiments, the palmar center is in the (S) configuration.

Generally as defined above, ^{each instance of R 9} is independently pendant oxy, C _1-6 hydroxy aliphatic, -R ² , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O) )N(R)OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C (O)NR ₂ or -N(R)S(O) ₂ R.

In some embodiments, R ⁸ is pendant oxy, -R ² , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ₂ or -N(R)S(O ) ₂ R.

In some embodiments, R ⁹ is a pendant oxy group. In some embodiments, R ⁹ is -R ² . In some embodiments, R ⁹ is optionally substituted C _1-6 aliphatic. In some embodiments, R ⁹ is C _1-6 hydroxy aliphatic. In some embodiments, R ⁹ is hydroxymethyl. In some embodiments, R ⁹ is hydroxyethyl. In some embodiments, R ⁹ is hydroxycyclobutyl. In some embodiments, R ⁹ is hydroxycyclobutyl. In some embodiments, R ⁹ is N,N-dimethylaminoethyl. In some embodiments, R ⁹ is a 3 to 7 membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R ^{9 is} selected from -OH, -OEt, -NH ₂ , NHEt, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholine Group, oxabutanyl, tetrahydrothiopiperanyl and tetrahydrofuranyl. In some embodiments, when L ¹ is not present, at least one R ⁹ is a pendant oxy group.

Generally as defined above, each instance of ^{R 10 is independently -R 2} , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O ) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -OC(O) R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ₂ or -N(R)S (O) ₂ R.

In some embodiments, R ¹⁰ is pendant oxy, -R ² , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ₂ or -N(R)S(O ) ₂ R.

Generally as defined above, m is 0-4. In some embodiments, m is zero. In some embodiments, m is 1 to 4. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.

Generally as defined above, n is 0-4. In some embodiments, n is zero. In some embodiments, n is 1 to 4. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 0 to 1. In some embodiments, n is 0-2. In some embodiments, n is 0-3.

Generally as defined above, p is 0-6. In some embodiments, p is zero. In some embodiments, p is 1 to 6. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 1 to 3. In some embodiments, p is 4. In some embodiments, p is 5. In some embodiments, p is 6.

Generally as defined above, q is 0-4. In some embodiments, q is zero. In some embodiments, q is 1 to 4. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3. In some embodiments, q is 4. In some embodiments, q is 0 to 1. In some embodiments, q is 0-2. In some embodiments, q is 0-3.

In certain embodiments, the present invention provides a compound of formula I , wherein when X is =N-, R ³ is phenyl.

In certain embodiments, the present invention provides a compound of formula I , II or III , wherein R ¹ and R ^1'are each hydrogen, thereby forming a compound of formula Ia , II-a or III-a , respectively:

Or a pharmaceutically acceptable salt thereof, wherein X, Y, ring A, L ¹ , L ^{1 '} , R ³ , R ⁴ , R ^4' , R ⁵ and R ^{5 'are} each as defined above and implemented as herein As mentioned in the examples, individually and in combination.

In certain embodiments, the present invention provides a compound of formula I , II , III or IV , wherein X is =N-, and Y is =C(R ⁶ )-; thereby forming formula Ib , II-b , Compounds of III-b or IV-b:

或其醫藥上可接受之鹽，其中環A、L¹、L^1’、R¹、R^1’、R³、R⁴、R^4’、R⁵、R^5’及R⁶各係如上文所定義及本文實施例中所述，單獨地及組合地。

Or a pharmaceutically acceptable salt thereof, wherein ring A, L ¹ , L ^{1 '} , R ¹ , R ^1' , R ³ , R ⁴ , R ^{4 '} , R ⁵ , R ^5' and R ^{6 are} each as above Defined and described in the examples herein, individually and in combination.

或其醫藥上可接受之鹽，其中環A、L¹、L^1’、R¹、R^1’、R³、R⁴、R^4’、R⁵、R^5’及R⁶各係如上文所定義及如本文實施例中所述，單獨地及組合地。 In certain embodiments, the present invention provides a compound of formula I , II , III or IV , wherein X is =C(R ⁶ )-; and Y is =N-, thereby forming formula Ic , II-c , Compounds of III-c or IV-c:

Or a pharmaceutically acceptable salt thereof, wherein ring A, L ¹ , L ^{1 '} , R ¹ , R ^1' , R ³ , R ⁴ , R ^{4 '} , R ⁵ , R ^5' and R ^{6 are} each as above Defined and as described in the Examples herein, individually and in combination.

或其醫藥上可接受之鹽，其中環A、L¹、L^1’、R¹、R^1’、R³、R⁴、R^4’、R⁵、R^5’及R⁶各係如上文所定義及如本文實施例中所述，單獨地及組合地。 In certain embodiments, the present invention provides a compound of formula I , II , III or IV , wherein X is =C(R ⁶ )-; and Y is =N ⁺ (→O ^- )-, thereby respectively forming formula Compounds of Ic- i , II-c- i , III-c- i or IV-c- i :

Or a pharmaceutically acceptable salt thereof, wherein ring A, L ¹ , L ^{1 '} , R ¹ , R ^1' , R ³ , R ⁴ , R ^{4 '} , R ⁵ , R ^5' and R ^{6 are} each as above Defined and as described in the Examples herein, individually and in combination.

或其醫藥上可接受之鹽，其中環A、L¹、L^1’、R¹、R^1’、R³、R⁴、R^4’、R⁵、R^5’及R⁶各係如上文所定義及如本文實施例中所述，單獨地及組合地。 In certain embodiments, the present invention provides a compound of formula I , II , III or IV , wherein X and Y are each =N-, thereby forming a compound of formula Id , II-d , III-d or IV-d , respectively Compound:

Or a pharmaceutically acceptable salt thereof, wherein ring A, L ¹ , L ^{1 '} , R ¹ , R ^1' , R ³ , R ⁴ , R ^{4 '} , R ⁵ , R ^5' and R ^{6 are} each as above Defined and as described in the Examples herein, individually and in combination.

In some embodiments, the present invention provides a compound of any one of formula Ib , Ic , II-b , II-c , III-b , III-c , IV-b or IV-c , wherein R ⁶ is hydrogen . In some embodiments, the present invention provides a compound of any one of formula Ib , Ic , II-b , II-c , III-b , III-c , IV-b, or IV-c , wherein R ⁶ is halogen . In some embodiments, the present invention provides a compound of any one of formula Ib , Ic , II-b , II-c , III-b , III-c , IV-b, or IV-c , wherein R ⁶ is fluorine . In some embodiments, the present invention provides a compound of any one of formula Ib , Ic , II-b , II-c , III-b , III-c , IV-b or IV-c , wherein R ⁶ is- CN.

In certain embodiments, the present invention provides a formula I , II , III , IV , Ia , II-a , III-a , Ib , II-b , III-b , IV-b , Ic , II-c , A compound of any one of III-c , IV-c , Id , II-d , III-d, or IV-d , wherein ring A is phenyl, pyridin-2-yl, pyridin-3-yl, or pyrazinyl , Pyridazinyl or pyrazol-4-yl.

或其醫藥上可接受之鹽，其中X、Y、L¹、L^1’、R¹、R^1’、R³、R⁴、R^4’、R⁵、R^5’、R⁷及m各係如上文所定義及如本文實施例中所述，單獨地及組合地。 In certain embodiments, the present invention provides a compound of one of formula I , II , III or IV , wherein ring A is phenyl, and L ¹ is -N(R ⁴ )- or -N(R ^4' ) -In the para position to form a compound of one of formula Ie , II-e , III-e and IV-e :

Or a pharmaceutically acceptable salt thereof, wherein X, Y, L ¹ , L ^{1 '} , R ¹ , R ^1' , R ³ , R ⁴ , R ^{4 '} , R ⁵ , R ^5' , R ⁷ and m each As defined above and as described in the examples herein, individually and in combination.

或其醫藥上可接受之鹽，其中X、Y、L¹、L^1’、R¹、R^1’、R³、R⁴、R^4’、R⁵、R^5’、R⁷及m各係如上文所定義及如本文實施例中所述，單獨地及組合地。 In certain embodiments, the present invention provides a compound of one of formula I , II , III or IV , wherein ring A is pyridin-2-yl, and L ¹ is -N(R ⁴ )- or -N(R ^4' )- to form a compound of formula If , II-f , III-f and IV-f :

Or a pharmaceutically acceptable salt thereof, wherein X, Y, L ¹ , L ^{1 '} , R ¹ , R ^1' , R ³ , R ⁴ , R ^{4 '} , R ⁵ , R ^5' , R ⁷ and m each As defined above and as described in the examples herein, individually and in combination.

或其醫藥上可接受之鹽，其中X、Y、L¹、L^1’、R¹、R^1’、R³、R⁴、R^4’、R⁵、R^5’、R⁷及m各係如上文所定義及如本文實施例中所述，單獨地及組合地。 In certain embodiments, the present invention provides a compound of one of formula I , II , III, or IV , wherein ring A is pyridin-3-yl, and L ¹ is -N(R ⁴ )- or -N(R ^4' )- to form a compound of one of formula Ig , II-g , III-g and IV-g :

Or a pharmaceutically acceptable salt thereof, wherein X, Y, L ¹ , L ^{1 '} , R ¹ , R ^1' , R ³ , R ⁴ , R ^{4 '} , R ⁵ , R ^5' , R ⁷ and m each As defined above and as described in the examples herein, individually and in combination.

或其醫藥上可接受之鹽，其中X、Y、L¹、L^1’、R¹、R^1’、R³、R⁴、R^4’、R⁵、R^5’、R⁷及m各係如上文所定義及如本文實施例中所述，單獨地及組合地。 In certain embodiments, the present invention provides a compound of one of formula I , II , III or IV , wherein ring A is pyridazinyl, and L ¹ is -N(R ⁴ )- or -N(R ^4' )- to form a compound of one of formula Ih , II-h , III-h and IV-h :

Or a pharmaceutically acceptable salt thereof, wherein X, Y, L ¹ , L ^{1 '} , R ¹ , R ^1' , R ³ , R ⁴ , R ^{4 '} , R ⁵ , R ^5' , R ⁷ and m each As defined above and as described in the examples herein, individually and in combination.

或其醫藥上可接受之鹽，其中X、Y、L¹、L^1’、R¹、R^1’、R³、R⁴、R^4’、R⁵、R^5’、R⁷及m各係如上文所定義及如本文實施例中所述，單 獨地及組合地。 In certain embodiments, the present invention provides a compound of one of formula I , II , III or IV , wherein ring A is pyrazinyl, and L ¹ is -N(R ⁴ )- or -N(R ^4' )- to form a compound of one of formula Ii , II-i , III-i and IV-i :

Or a pharmaceutically acceptable salt thereof, wherein X, Y, L ¹ , L ^{1 '} , R ¹ , R ^1' , R ³ , R ⁴ , R ^{4 '} , R ⁵ , R ^5' , R ⁷ and m each As defined above and as described in the examples herein, individually and in combination.

或其醫藥上可接受之鹽，其中X、Y、L¹、L^1’、R¹、R^1’、R³、R⁴、R^4’、R⁵、R^5’、R⁷及m各係如上文所定義及如本文實施例中所述，單獨地及組合地。 In certain embodiments, the present invention provides a compound of one of formula I , II , III or IV , wherein ring A is pyrazol-4-yl, and L ¹ is -N(R ⁴ )- or -N( R ^4' )- to form a compound of one of formula Ij , II-j , III-j and IV-j :

Or a pharmaceutically acceptable salt thereof, wherein X, Y, L ¹ , L ^{1 '} , R ¹ , R ^1' , R ³ , R ⁴ , R ^{4 '} , R ⁵ , R ^5' , R ⁷ and m each As defined above and as described in the examples herein, individually and in combination.

或其醫藥上可接受之鹽，其中X、Y、環A、L¹、L^1’、R¹、R^1’、R⁴、R⁴、R^5’、R⁵、R^8’及n各係如上文所定義及如本文實施例中所述，單獨地及組合地。 In certain embodiments, the present invention provides a compound of one of formula I , II , III or IV , wherein R ³ is phenyl, pyrrolidinyl or piperidinyl. In certain embodiments, the present invention provides a compound of one of formula I , II , III, or IV , wherein R ³ is phenyl, thereby forming a compound of formula Ik , II-k , III-k, or IV-k , respectively :

Or a pharmaceutically acceptable salt thereof, wherein X, Y, ring A, L ¹ , L ^1' , R ¹ , R ^1' , R ⁴ , R ⁴ , R ^5' , R ⁵ , R ^8'and n are each As defined above and as described in the examples herein, individually and in combination.

In certain embodiments, the present invention provides a compound of one of formula I , II , III, or IV , or a pharmaceutically acceptable salt thereof, wherein n is 1 to 3, and at least one R ⁸ substituent is the point of attachment The neighbor. In certain embodiments, the present invention provides a compound of one of formula I , II , III, or IV , or a pharmaceutically acceptable salt thereof, wherein n is 1. In certain embodiments, the present invention provides a compound of one of formula I , II , III, or IV , or a pharmaceutically acceptable salt thereof, wherein n is 2. In certain embodiments, the present invention provides a compound of one of formula I , II , III, or IV , or a pharmaceutically acceptable salt thereof, wherein n is 2, and at least one R ⁸ is halogen. In certain embodiments, the present invention provides a compound of one of formula I , II , III, or IV , or a pharmaceutically acceptable salt thereof, wherein n is 2, and at least one R ⁸ is fluorine.

或其醫藥上可接受之鹽，其中X、Y、環A、L¹、L^1’、R¹、R^1’、R⁴、R⁴、R^5’及R⁵各係如上文所定義及如本文實施例中所述，單獨地及組合地。 In certain embodiments, the present invention provides a compound of one of formula Ik , II-k , III-k, or IV-k , wherein n is 2, and each R ⁸ is fluorine, thereby forming formulas Il , II- l , III-l or IV-l compound:

Or a pharmaceutically acceptable salt thereof, wherein X, Y, ring A, L ¹ , L ^{1 '} , R ¹ , R ^1' , R ⁴ , R ⁴ , R ^{5 '} and R ^{5 are} each as defined above and As described in the examples herein, individually and in combination.

或其醫藥上可接受之鹽，其中X、Y、環A、R¹、R^1’、R³、R⁴、R^4’、R⁵及R^5’各係如上文所定義及如本文實施例中所述，單獨地及組合地。 In certain embodiments, the present invention provides a compound of one of formula I , III or IV ^{, wherein L 1} is a covalent bond or -C(O)-, thereby forming formula Im , III-m or IV-m, respectively The compound:

Or a pharmaceutically acceptable salt thereof, wherein X, Y, ring A, R ¹ , R ^{1 '} , R ³ , R ⁴ , R ^4' , R ⁵ and R ^{5 'are} each as defined above and implemented as herein As mentioned in the examples, individually and in combination.

或其醫藥上可接受之鹽，其中X、Y、環A、R¹、R^1’、R³、R⁴、R^4’、R⁵及R^5’各係如上文所定義及如本文實施例中所述，單獨地及組合地。 In certain embodiments, the present invention provides a compound of one of formula I , III or IV ^{, wherein L 1} is -C(O)-, thereby forming a compound of formula In , III-n or IV-n , respectively:

Or a pharmaceutically acceptable salt thereof, wherein X, Y, ring A, R ¹ , R ^{1 '} , R ³ , R ⁴ , R ^4' , R ⁵ and R ^{5 'are} each as defined above and implemented as herein As mentioned in the examples, individually and in combination.

或其醫藥上可接受之鹽，其中環A、R¹、R^1’、R³、R⁴、R^4’、R⁵、R^5’及R⁶各係如上文所定義及如本文實施例中所述，單獨地及組合地。 In certain embodiments, the present invention provides compounds of formula In, compound III-n, or IV-n in the one, wherein X is = C (R ⁶⁾ -, and Y is = N-, thereby forming Formula Io, Compounds of III-o or IV-o:

Or a pharmaceutically acceptable salt thereof, wherein ring A, R ¹ , R ^{1 '} , R ³ , R ⁴ , R ^4' , R ⁵ , R ^{5 '} and R ^{6 are} each as defined above and as in the examples herein As described in, individually and in combination.

或其醫藥上可接受之鹽，其中環A、R¹、R^1’、R³、R⁴、R^4’、R⁵、R^5’及R⁶各係如上文所定義及如本文實施例中所述，單獨地及組合地。 In certain embodiments, the present invention provides a compound of one of formula Im , III-m, or IV-m , wherein X is =C(R ⁶ )-, and Y is =N-, thereby forming formula Ip , III-p or IV- p compound:

Or a pharmaceutically acceptable salt thereof, wherein ring A, R ¹ , R ^{1 '} , R ³ , R ⁴ , R ^4' , R ⁵ , R ^{5 '} and R ^{6 are} each as defined above and as in the examples herein As described in, individually and in combination.

Exemplary compounds of the present invention are listed in Table 1 below.

In some embodiments, the method uses the compounds listed in Table 1 above or their pharmaceutically acceptable salts. In some embodiments, the present invention provides the compounds listed in Table 1 above or pharmaceutically acceptable salts thereof. In some embodiments, the present invention provides a pharmaceutical composition comprising the compounds listed in Table 1 above or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, excipient or diluent.

Without wishing to be bound by any particular theory, it is believed that the proximity of the inhibitor compound or the side chain portion of the inhibitor compound to the desired water facilitates replacement or destruction by the inhibitor compound or the side chain portion of the inhibitor compound The water. In some embodiments, the water molecule replaced or destroyed by the inhibitor compound or the side chain part of the inhibitor compound is unstable water molecular.

In certain embodiments, the method uses a complex containing TYK2 and an inhibitor, wherein at least one unstable water of TYK2 is replaced or destroyed by the inhibitor. In some embodiments, at least two selected unstable waters are replaced or destroyed by the inhibitor.

4. General methods for providing the compounds of the present invention

The compounds of the present invention can basically be prepared or isolated by the synthetic and/or semi-synthetic methods known to those skilled in the art for similar compounds and the methods described in detail in the examples herein.

5. Purpose, deployment and investment

Pharmaceutically acceptable composition

According to another embodiment, the present invention provides a composition comprising a compound of the present invention or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant or vehicle. The amount of the compound in the composition of the present invention is such that it effectively and measurably inhibits TYK2 protein kinase or its mutants in biological samples or patients. In certain embodiments, the amount of the compound in the composition of the present invention is such that it effectively and measurably inhibits TYK2 protein kinase or its mutants in biological samples or patients. In certain embodiments, the composition of the present invention is formulated for administration to patients in need of the composition. In some embodiments, the composition of the invention is formulated for oral administration to a patient.

As used herein, the term "patient" means an animal, preferably a mammal, and most preferably a human.

The term "pharmaceutically acceptable carrier, adjuvant or vehicle" refers to a non-toxic carrier, adjuvant or vehicle that will not destroy the pharmacological activity of the compound to which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that can be used in the composition of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffers Substances (such as phosphate), glycine, sorbic acid, potassium sorbate, saturated vegetable fatty acids, partial glyceride mixtures, water, salts or electrolytes, such as protamine sulfate Salt, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, carboxymethyl cellulose Sodium, polyacrylate, wax, polyethylene-polyoxypropylene-block polymer, polyethylene glycol and lanolin.

"Pharmaceutically acceptable derivative" means any non-toxic salt, ester, ester salt or other derivative of the compound of the present invention, which can directly or indirectly provide the compound of the present invention or its derivatives when administered to the recipient. Metabolites or residues that inhibit activity.

As used herein, the term "metabolite or residue with inhibitory activity" means that its metabolite or residue is also an inhibitor of TYK2 protein kinase or its mutants.

The composition of the present invention can be administered orally, parenterally, by inhalation spray, topically, transrectally, transnasally, transbuccally, transvaginally, or via implantable containers. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. These compositions are preferably administered orally, intraperitoneally or intravenously. The sterile injectable form of the composition of the present invention may be an aqueous or oily suspension. These suspensions can be formulated according to techniques known in the art using appropriate dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are usually used as solvents or suspending media.

For this purpose, any non-irritating fixed oil can be used, including synthetic monoglycerides or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives, can be used in the preparation of injectables, just as natural pharmaceutically acceptable oils such as olive oil or castor oil can also be used, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as carboxymethyl cellulose, or similar dispersants commonly used to formulate pharmaceutically acceptable dosage forms (including emulsions and suspensions). Commonly used in the manufacture of medically acceptable solids, Other commonly used surfactants in liquid or other dosage forms, such as Tween, Span, and other emulsifiers or bioavailability enhancers, can also be used for formulation purposes.

The pharmaceutically acceptable composition of the present invention can be administered orally in any orally acceptable dosage form, including but not limited to capsules, lozenges, aqueous suspensions or solutions. In the case of tablets for oral use, commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate are usually also added. For oral administration in capsule form, diluents that can be used include lactose and dried corn starch. When an aqueous suspension is required for oral use, the active ingredient is combined with emulsifying and suspending agents. If necessary, certain sweetening, flavoring or coloring agents can also be added.

Alternatively, the pharmaceutically acceptable composition of the present invention may be administered in the form of suppositories for rectal administration. These can be made by mixing the medicament with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and will therefore melt in the rectum to release the drug . Such materials include cocoa butter, beeswax and polyethylene glycol.

The pharmaceutically acceptable composition of the present invention can also be administered locally, especially when the target of treatment includes areas or organs that can be easily accessed by topical application, including diseases of the eyes, skin or lower intestinal tract. Appropriate local formulations are easily made for each of these areas or organs.

Topical application for the lower intestinal tract can be achieved with rectal suppository formulations (see above) or with appropriate enema formulations. A topical transdermal patch can also be used.

For topical application, the provided pharmaceutically acceptable composition can be formulated in a suitable ointment, which contains the active ingredients suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of the present invention include, but are not limited to, mineral oil, liquid paraffin, white paraffin, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the provided pharmaceutically acceptable composition can be formulated in a suitable lotion or cream, which contains the active ingredients suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, ten Hexaalkyl ester wax, cetyl stearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the pharmaceutically acceptable composition provided can be formulated as an ultrafine suspension in isotonic, pH-adjusted sterile saline, or preferably isotonic, pH-adjusted sterile saline In the solution, with or without preservatives, such as benzalkonium chloride. Alternatively, for ophthalmic use, a pharmaceutically acceptable composition may be formulated in an ointment, such as paraffin wax.

The pharmaceutically acceptable composition of the present invention can also be administered by nasal aerosol or inhalation. This kind of composition is made according to the well-known technology in the pharmaceutical formulation technology, and can be made into a solution in saline, using benzyl alcohol or other appropriate preservatives, absorption enhancers to enhance bioavailability, fluorocarbons and / Or other conventional co-solvents or dispersants.

Most preferably, the pharmaceutically acceptable composition of the present invention is formulated for oral administration. Such formulations can be administered with or without food. In some embodiments, the pharmaceutically acceptable composition of the present invention is not administered with food. In other embodiments, the pharmaceutically acceptable composition of the present invention is administered with food.

The amount of the compound of the invention that can be combined with carrier materials to produce a composition in a single dosage form will vary depending on the subject being treated and the particular mode of administration. Preferably, the provided compositions should be formulated so that a dose of the inhibitor between 0.01 to 100 mg/kg body weight/day can be administered to patients receiving these compositions.

It should also be understood that the specific dosage and treatment regimen for any specific patient will depend on many factors, including the activity of the specific compound used, age, weight, general health, gender, diet, administration time, excretion rate, drug combination, and The judgment of the treating physician and the severity of the specific disease being treated. The amount of the compound of the invention in the composition will also depend on the specific compound in the composition.

Uses of compounds and pharmaceutically acceptable compositions

The compounds and compositions described herein can generally be used to inhibit the kinase activity of one or more enzymes. In some embodiments, the kinase inhibited by the compounds and methods of the present invention is TYK2.

TYK2 is a non-receptor tyrosine kinase member of the Janus Kinase (JAK) family of protein kinases. The mammal JAK family consists of four members: TYK2, JAK1, JAK2 and JAK3. JAK proteins (including TYK2) are necessary for cytokine signaling. TYK2 is related to the cytoplasmic domains of type I and type II cytokine receptors, and interferon type I and type III receptors, and is activated by these receptors when it binds to cytokines. The cytokines involved in TYK2 activation include interferons (e.g., IFN-α, IFN-β, IFN-κ, IFN-δ, IFN-ε, IFN-τ, IFN-ω and IFN-ζ (also known as restriction factors) ), and interleukins (e.g. IL-4, IL-6, IL-10, IL-11, IL-12, IL-13, IL-22, IL-23, IL-27, IL-31, oncostatin M , Ciliary neurotrophic factor, cardiotrophin 1, cardiotrophin-like cytokines and LIF). Velasquez et al., "A protein kinase in the interferon α/β signaling pathway," Cell (1992) 70:313; Stahl et al. "Association and activation of Jak-Tyk kinases by CNTF-LIF-OSM-IL-6β receptor components," Science (1994) 263:92; Finbloom et al., "IL-10 induces the tyrosine phosphorylation of Tyk2 and Jak1 and the differential assembly of Stat1 and Stat3 complexes in human T cells and monocytes, "J. Immunol. (1995) 155: 1079; Bacon et al., "Interleukin 12(IL-12)induces tyrosine phosphorylation of Jak2 and Tyk2: differential use of Janus family kinases by IL-2 and IL-12, "J. Exp. Med. (1995) 181: 399; Welham et al., "Interleukin-13 signal transduction in lymphohemopoietic cells: similarities and differences in signal transduction with interleukin-4 and Insulin," J. Biol. Chem. (1995) 270: 12286; Parham et al., "A receptor for the heterodimeric cytokine IL-23 is composed of IL-12 Rβ1 and a novel cytokine receptor subunit, IL-23R," J. Immunol. (2002) 168:5699. The activated TYK2 then continues to phosphorylate other signaling proteins, such as members of the STAT family, including STAT1, STAT2, STAT4, and STAT6.

The activation of TYK2 with IL-23 has been linked to inflammatory bowel disease (IBD), Crohn's disease and ulcerative colitis. Duerr et al., "A Genome-Wide Association Study Identifies IL23R as an Inflammatory Bowel Disease Gene," Science (2006) 314: 1461-1463. As a downstream effector of IL-23, TYK2 also plays a role in psoriasis, ankylosing spondylitis and Behçet's disease. Cho et al., "Genomics and the multifactorial nature of human auto-immune disease," N. Engl. J. Med (2011) 365:1612-1623; Cortes et al., "Identification of multiple risk variants for ankylosing spondylitis through high- density genotyping of immune-related loci,"Nat.Genet.(2013)45(7):730-738; Remmers et al., "Genome-wide association study identifies variants in the MHC class I,IL10,and IL23R-IL12RB2 regions associated with Behçet's disease, "Nat. Genet. (2010) 42: 698-702. A genome-wide association study of 2,622 individuals with psoriasis determined the association between disease susceptibility and TYK2. Strange et al., "A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1," Nat. Genet. (2010) 42: 985-992. Gene knockout or inhibition of TYK2 with a tyrosine phosphorylation inhibitor significantly reduced IL-23 and IL-22-induced dermatitis. Ishizaki et al., "Tyk2 is a therapeutic target for psoriasis-like skin inflammation," Intl. Immunol. (2013), doi: 10.1093/intimm/dxt062.

TYK2 also plays a role in respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), lung cancer and cystic fibrosis. Goblet cell hyperplasia (GCH) and mucus hypersecretion are mediated by IL-13-induced TYK2 activation, which in turn activates STAT6. Zhang et al., "Docking protein Gab2 regulates mucin expression and goblet cell hyperplasia through TYK2/STAT6 pathway," FASEB J. (2012) 26:1-11.

Decreased TYK2 activity leads to protection of joints from collagen antibody-induced arthritis (a human rheumatoid arthritis model). In mechanism, the decrease of Tyk2 activity reduces the production of T _h 1/T _h 17-related cytokines, matrix metalloproteinases, and other key inflammation markers. Ishizaki et al., "Tyk2 deficiency protects joints against destruction in anti-type II collagen antibody-induced arthritis in mice," Intl. Immunol. (2011) 23(9): 575-582.

Compared with controls, TYK2 knockout mice showed complete resistance in experimental autoimmune encephalomyelitis (EAE, an animal model of multiple sclerosis (MS)), and did not infiltrate CD4 T cells in the spine , Indicating that TYK2 is essential in the development of the pathogenic CD4-mediated disease of MS. Oyamada et al., "Tyrosine Kinase 2 Plays Critical Roles in the Pathogenic CD4 T Cell Responses for the Development of Experimental Autoimmune Encephalomyelitis," J. Immunol. (2009) 183:7539-7546. This supports earlier studies linking increased TYK2 performance with MS susceptibility. Ban et al., "Replication analysis identifies TYK2 as a multiple sclerosis susceptibility factor," Eur J. Hum. Genet. (2009) 17: 1309-1313. The loss-of-function mutation of TYK2 results in decreased demyelination of neurons and increased remyelination, which further indicates that TYK2 inhibitors play a role in the treatment of MS and other CNS demyelinating disorders.

TYK2 is the only signalling messenger shared by IL-12 and IL-23. TYK2 gene knockout reduces the thickness of the footpads induced by methylated BSA injection, imiquimod-induced psoriasis-like skin inflammation, and sodium dextran sulfate or 2,4,6-trinitro in mice Benzenesulfonic acid-induced colitis.

Research on the joint linkage and association between various type I IFN signaling genes and systemic lupus erythematosus (SLE, an autoimmune disease) shows that the loss-of-function mutation of TYK2 and the prevalence of SLE in families with infected members have decreased. Strong and significant correlation. Sigurdsson et al., "Polymorphisms in the Tyrosine Kinase 2 and Interferon Regulatory Factor 5 Genes Are Associated with Systemic Lupis Erythematosus, "Am. J. Hum. Genet. (2005) 76: 528-537. Genome-wide association studies on individuals with SLE show that compared with the uninfected group, there is a highly significant correlation between the TYK2 locus and SLE. Graham et al., "Association of NCF2, IKZF1, IRF8, IFIH1, and TYK2 with Systemic Lupus Erythematosus," PLoS Genetics (2011) 7(10): e1002341.

It has been shown that TYK2 plays an important role in maintaining tumor surveillance, and TYK2 knockout mice have impaired cytotoxic T cell responses and accelerated tumor development. However, these effects are related to the effective suppression of natural killer (NK) and cytotoxic T lymphocytes, indicating that TYK2 inhibitors will be extremely suitable for the treatment of autoimmune diseases or transplant rejection. Although other JAK family members (such as JAK3) have similar roles in the immune system, TYK2 has been suggested as an excellent target because it participates in less and more closely related signaling pathways, resulting in fewer off-target effects. Simma et al., "Identification of an Indispensable Role for Tyrosine Kinase 2 in CTL-Mediated Tumor Surveillance," Cancer Res. (2009) 69:203-211.

However, in contradiction with the reduction in tumor monitoring observed by Simma et al., studies on T-cell acute lymphoblastic leukemia (T-ALL) have shown that T-ALL is highly transduced via STAT1-mediated signal transduction via TYK2. IL-10 is dependent on the survival of cancer cells through the up-regulation of the anti-apoptotic protein BCL2. Attenuating the performance of TYK2 but not other JAK family members can slow cell growth. Specific activating mutations against TYK2 that promote the survival of cancer cells include their mutations against the FERM domain (G36D, S47N and R425H), the JH2 domain (V731I) and the kinase domain (E957D and R1027H). However, it has also been determined that the kinase function of TYK2 is required to increase the survival of cancer cells because the TYK2 enzyme characterized by kinase death mutations (M978Y or M978F) other than the activating mutation (E957D) results in the inability to transform. Sanda et al., "TYK2-STAT1-BCL2 Pathway Dependence in T-Cell Acute Lymphoblastic Leukemia," Cancer Disc. (2013) 3(5): 564-577.

Therefore, selective inhibition of TYK2 has been suggested as a suitable target for patients with IL-10 and/or BCL2-addiction tumors (such as 70% of adult T-cell leukemia cases). Fontan et al., "Discovering What Makes STAT Signaling TYK in T-ALL," Cancer Disc. (2013) 3:494-496.

It has been shown that STAT3 signal transmission mediated by TYK2 also mediates neuronal cell death caused by amyloid-β (Aβ) peptide. After administration of Aβ, the decrease in TYK2 phosphorylation of STAT3 leads to a decrease in neuronal cell death, and an increase in STAT3 phosphorylation has been observed in the brains of patients with Alzheimer's disease after death. Wan et al., "Tyk/STAT3 Signaling Mediates β-Amyloid-Induced Neuronal Cell Death: Implications in Alzheimer’s Disease," J. Neurosci. (2010) 30(20): 6873-6881.

Inhibition of the JAK-STAT signaling pathway is also involved in hair growth and the reversal of alopecia related to alopecia areata. Xing et al., "Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition," Nat. Med. (2014) 20: 1043-1049; Harel et al., "Pharmacologic inhibition of JAK-STAT signaling promotes hair growth, "Sci.Adv. (2015) 1(9): e1500973.

Therefore, compounds that inhibit the activity of TYK2 are beneficial, especially those that are selective for JAK2. These compounds should be delivered to favorably treat one or more of the conditions described herein without the pharmacological reactions associated with the side effects associated with the inhibition of JAK2.

Although TYK2 inhibitors are known in the art, there is still a need to provide novel inhibitors with more effective or beneficial medical-related properties. For example, compounds with improved activity, selectivity against other JAK kinases (especially JAK2), and ADMET (absorption, distribution, metabolism, excretion and/or toxicity) properties. Therefore, in some embodiments, the present invention provides TYK2 inhibitors showing selectivity for JAK2.

The activity of the compounds used as inhibitors of TYK2 or its mutants in the present invention can be analyzed in vitro, in vivo, or in cell lines. In vitro analysis includes the determination of phosphorylation activity and/or subsequent function results of inhibiting activation of TYK2 or its mutants, or ATP Analysis of enzyme activity. Alternate in vitro analysis quantifies the ability of inhibitors to bind to TYK2. Inhibitor binding can be determined by radiolabeling the inhibitor before binding, separating the inhibitor/TYK2 complex, and measuring the amount of radiolabel bound. Alternatively, inhibitor binding can be determined by conducting a competition experiment, in which a novel inhibitor is incubated with TYK2 bound to a known radioligand. Representative in vitro and in vivo analyses that can be used to analyze TYK2 inhibitors include those described and disclosed in, for example, various documents incorporated herein by reference in their entirety. The following examples list detailed conditions for the analysis of compounds used as inhibitors of TYK2 or its mutants in the present invention.

As used herein, the term "treatment" refers to reversing, alleviating, delaying the onset of, or inhibiting the progression of, a disease or disorder as described herein, or one or more of its symptoms. In some embodiments, treatment may be administered after one or more symptoms appear. In other embodiments, treatment can be administered when asymptomatic. For example, treatment may be administered to susceptible individuals before the onset of symptoms (e.g., based on history of symptoms and/or based on genetic or other susceptibility factors). Treatment can also be continued after the symptoms are eliminated, for example to prevent or delay its recurrence.

The provided compounds are TYK2 inhibitors and can therefore be used to treat one or more conditions related to the activity of TYK2 or its mutants. Therefore, in certain embodiments, the present invention provides a method for treating TYK2-mediated conditions, which includes the step of administering a compound of the present invention or a pharmaceutically acceptable composition thereof to a patient in need thereof.

As used herein, the term "TYK2-mediated" disease, disease and/or condition as used herein means any disease or other harmful condition in which TYK2 or its mutants are known to function. Therefore, another embodiment of the present invention relates to treating or reducing the severity of one or more diseases in which TYK2 or its mutants are known to work. These TYK2-mediated diseases include (but are not limited to) autoimmune diseases, inflammatory diseases, proliferative diseases, endocrine diseases, neurological diseases, and transplant-related diseases.

In some embodiments, the present invention provides a method of treating one or more conditions, The conditions are selected from autoimmune diseases, inflammatory diseases, proliferative diseases, endocrine diseases, neurological diseases, and transplant-related diseases. The method includes administering an effective amount of the compound of the present invention to a patient in need thereof Or a pharmaceutical composition of a pharmaceutically acceptable salt thereof.

In some embodiments, the disorder is an autoimmune disease. In some embodiments, the disorder is selected from type 1 diabetes, systemic lupus erythematosus, multiple sclerosis, psoriasis, Beside's disease, POEMS syndrome, Crohn's disease, ulcerative colitis, and inflammatory bowel sick.

In some embodiments, the condition is an inflammatory disease. In some embodiments, the inflammatory disease is rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis, hepatomegaly, Crohn's disease, ulcerative colitis, inflammatory bowel disease.

In some embodiments, the condition is a proliferative disease. In some embodiments, the proliferative disease is hematological cancer. In some embodiments, the proliferative disease is leukemia. In some embodiments, the leukemia is T cell leukemia. In some embodiments, the T-cell leukemia is T-cell acute lymphoblastic leukemia (T-ALL). In some embodiments, the proliferative disease is polycythemia vera, myelofibrosis, primary or thrombocythemia.

In some embodiments, the disorder is an endocrine disease. In some embodiments, the endocrine disease is polycystic ovary syndrome, Crouzon's syndrome, or type 1 diabetes.

In some embodiments, the disorder is a neurological disease. In some embodiments, the neurological disease is Alzheimer's disease.

In some embodiments, the proliferative disease is associated with one or more activating mutations in TYK2. In some embodiments, the activating mutation of TYK2 is a mutation of the FERM domain, JH2 domain, or kinase domain. In some embodiments, the activating mutation of TYK2 is selected from G36D, S47N, R425H, V731I, E957D and R1027H.

In some embodiments, the condition is related to transplantation. In some embodiments, the transplant-related disorder is transplant rejection or graft-versus-host disease.

In some embodiments, the condition is related to type I interferon, IL-10, IL-12, or IL-23 signaling. In some embodiments, the condition is related to type I interferon signaling. In some embodiments, the condition is related to IL-10 signaling. In some embodiments, the condition is related to IL-12 signaling. In some embodiments, the condition is related to IL-23 signaling.

The compounds of the present invention can also be used to treat inflammatory or allergic conditions of the skin, such as psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, herpetic dermatitis, scleroderma, vitiligo , Hypersensitivity vasculitis, urticaria, bullous pemphigoid, lupus erythematosus, systemic lupus erythematosus, pemphigus vulgaris, pemphigus phyllodes, paraneoplastic pemphigus, acquired bullous epidermis Lax, acne vulgaris and other inflammatory or allergic conditions of the skin.

The compounds of the present invention can also be used to treat other diseases or conditions, such as diseases or conditions with inflammatory components, for example, to treat diseases and conditions of the eye (such as ocular allergy, conjunctivitis, keratoconjunctivitis sicca and vernal conjunctivitis), Diseases affecting the nose (including allergic rhinitis) and inflammatory diseases involving autoimmune reactions or autoimmune components or causes, including autoimmune hematological disorders (such as hemolytic anemia, aplastic anemia, pure Erythrocyte anemia and idiopathic thrombocytopenia), systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Stephen-Johnson syndrome, idiopathic sprue inflammatory diarrhea, autoimmune inflammatory bowel disease (such as ulcerative colitis and Crohn's disease), irritable bowel syndrome, celiac disease, periodontitis, transparent lung Membranous disease, nephropathy, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine ophthalmopathy, Grave's disease, sarcoidosis, alveolitis, chronic allergic pneumonia, multiple sclerosis , Primary biliary cirrhosis, uveitis (anterior and posterior), sjogren syndrome, keratoconjunctivitis sicca and Vernal keratoconjunctivitis, pulmonary interstitial fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, cryptopyrin-related cycle syndrome, nephritis, vasculitis, diverticulitis, interstitial cystitis, glomerular kidney (With and without renal disease syndrome, such as primary renal syndrome or minimal change nephropathy), chronic granulomatous disease, endometriosis, leptospirosis nephropathy, glaucoma, retinal disease, aging, headache, pain , Complex area pain syndrome, cardiac hypertrophy, muscle atrophy, catabolism disorders, obesity, fetal growth retardation, hypercholesterolemia, heart disease, chronic heart failure, mesothelioma, aspiration ectodermal dysplasia, Behcet Disease, pigment disorders, Paget's disease, pancreatitis, hereditary periodic fever syndrome, asthma (allergic and non-allergic, mild, moderate, severe, bronchial and exercise-induced), acute lung injury , Acute Respiratory Distress Syndrome, Tropical Eosinophilia, Hypersensitivity, Allergic Reaction, Sinusitis, Eye Allergy, Diseases Caused by Silica, COPD (Reducing Damage, Airway Inflammation, Bronchial Hyperresponsiveness, Severe (Plastic or disease progression), lung disease, cystic fibrosis, acid-induced lung injury, pulmonary hypertension, polyneuropathy, cataract, muscle inflammation with systemic sclerosis, inclusion body myositis, myasthenia gravis, thyroiditis, AIDS Addison's disease, lichen planus, type 1 or type 2 diabetes, appendicitis, atopic dermatitis, asthma, allergy, blepharitis, bronchiolitis, bronchitis, mucocystitis, cervicitis, bile duct Inflammation, cholecystitis, chronic transplant rejection, colitis, conjunctivitis, Crohn’s disease, cystitis, lacrimal gland inflammation, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, small bowel and colon Inflammation, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, Henoch-Schonlein purpura, hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial Pulmonary disease, laryngitis, mastitis, meningitis, myelitis myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, mumps, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, Pneumonia, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, Blood vessel Inflammation or vulvitis.

In certain embodiments, the present invention provides a method of treating alopecia areata.

In some embodiments, the inflammatory diseases that can be treated according to the method of the present invention are selected from acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, Systemic juvenile idiopathic arthritis (SJIA), cryptothermin-related cycle syndrome (CAPS) and osteoarthritis.

In some embodiments, the inflammatory disease that can be treated according to the method of the present invention is a disease mediated by _{T h} 1 or T _{h 17.} In some embodiments, the _Th 17 mediated disease is selected from systemic lupus erythematosus, multiple sclerosis, and inflammatory bowel disease (including Crohn's disease or ulcerative colitis).

In some embodiments, the inflammatory diseases that can be treated according to the method of the present invention are Sjogren’s syndrome, allergies, osteoarthritis, eye conditions (such as eye allergies, conjunctivitis, keratoconjunctivitis sicca and vernal conjunctivitis) and those affecting the nose. Diseases (such as allergic rhinitis).

In addition, the present invention provides the use of a compound as defined herein or a pharmaceutically acceptable salt, or hydrate or solvate thereof, for the preparation for the treatment of autoimmune diseases, inflammatory diseases or proliferative diseases or usually together with Medicament for the symptoms of transplantation.

Combination therapy

Depending on the specific condition or disease to be treated, other therapeutic agents usually administered to treat the condition can be administered in combination with the compounds and compositions of the present invention. As used herein, other therapeutic agents that are usually administered to treat a particular disease or condition are considered "applicable to the disease or condition being treated."

In certain embodiments, the provided combination or composition thereof is administered in combination with another therapeutic agent.

Examples of other agents that can also be combined with the combination of the present invention include but are not limited to: for the treatment of Alzheimer's disease, such as Aricept ^® and Excelon ^® ; for the treatment of HIV, such as ritonavir; For the treatment of Parkinson's disease, such as L-DOPA/Carbidopa, entacapone, ropinrole, pramipexole, bromide Bromocriptine, pergolide, trihexephendyl and amantadine; agents for the treatment of multiple sclerosis (MS), such as beta interferon (such as Avonex ^® and Rebif ^® ), Copaxone ^® and mitoxantrone (mitoxantrone); for the treatment of asthma, such as albuterol (albuterol) and Singulair ^® ; drugs for the treatment of schizophrenia, such as zyprexa (zyprexa), risperdal (risperdal), color Seroquel and haloperidone; anti-inflammatory agents such as corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide and sulfasalazine; Immunomodulatory and immunosuppressive agents, such as cyclosporin, tacrolimus, rapamycin, mycophenolate mofetil, interferon, corticosteroid, Cyclophosphamide, azathioprine and sulfasalazine; neurotrophic factors, such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anticonvulsants, ion channel blockers, rilulu Riluzole and anti-Parkinson's agents; agents for the treatment of cardiovascular diseases, such as β-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers and statins; treatment Drugs for liver disease, such as corticosteroids, cholestyramine, interferon, and antiviral agents; drugs for treating blood disorders, such as corticosteroids, anti-leukemia agents, and growth factors; drugs that prolong or improve pharmacokinetics, such as cells Pigment P450 inhibitors (ie, metabolic breakdown inhibitors) and CYP3A4 inhibitors (for example, ketokenozole and ritonavir), and agents for treating immunodeficiency, such as gamma globulin.

In certain embodiments, the combination therapy of the present invention or a pharmaceutically acceptable composition thereof is administered in combination with a monoclonal antibody or siRNA therapeutic agent.

These other agents can be administered separately from the combination therapy provided as part of a multiple dosing regimen. Alternatively, these agents may be part of a single dosage form, mixed with the compound of the invention in a single composition. If the drug is administered as part of a multiple-dose schedule, then The two active agents can be provided simultaneously, sequentially, or within a period of time (usually within five hours of each other).

As used herein, the term "combination" and related terms refer to the simultaneous or sequential administration of the therapeutic agents of the invention. For example, the combination of the present invention and another therapeutic agent can be administered simultaneously or sequentially in separate unit dosage forms, or together in a single unit dosage form.

The amount of other therapeutic agent present in the composition of the present invention will not exceed the amount normally administered in a composition containing the therapeutic agent as the sole active agent. Preferably, the amount of the other therapeutic agent in the currently disclosed composition will be in the range of about 50% to 100% of the amount normally present in a composition containing the agent as the only therapeutically active agent.

In one embodiment, the present invention provides a composition containing a compound of formula I and one or more other therapeutic agents. The therapeutic agent may be administered with the compound of formula I , or may be administered before or after the compound of formula I is administered. Suitable therapeutic agents are described in further detail below. In certain embodiments, the compound of formula I can be up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours before administration of the therapeutic agent. , 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours or 18 hours. In other embodiments, the compound of formula I can be up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, Administer at 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours.

In another embodiment, the present invention provides a method of treating inflammatory diseases, disorders, or conditions by administering a compound of formula I and one or more other therapeutic agents to patients in need thereof. These other therapeutic agents may be small molecules or recombinant biological agents, and include, for example, acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDS) (such as aspirin, ibuprofen, naproxen). ), etodolac (Lodine®) and celecoxib (celecoxib), colchicine (Colcrys®), corticosteroids (such as prednisone, prednisolone), (Methylprednisolone, hydrocortisone, etc.), probenecid, allopurinol, febuxostat (Uloric®), sulfasalazine ( Azulfidine®), antimalarial drugs such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), methotrexate (Rheumatrex®), gold salts (such as gold thioglucose (Solganal®), gold thiomalate ( Myochrysine® and auranofin (Ridaura®)), D-penicillamine (Depen® or Cuprimine®), azathioprine (Imuran®), cyclophosphamide (Cytoxan®), tumor Chlorambucil (Leukeran®), cyclosporine (Sandimmune®), leflunomide (Arava®), and ``anti-TNF'' agents such as etanercept (Enbrel®) , Infliximab (Remicade®), golimumab (Simponi®), pegylated certolizumab pegol (Cimzia®) and adalimumab (adalimumab) ( Humira®), ``anti-IL-1'' agents such as anakinra (Kineret®) and rilonacept (Arcalyst®), canakinumab (Ilaris®), anti- Jak inhibitors such as tofacitinib, antibodies such as rituximab (Rituxan®), ``anti-T cell'' agents such as abatacept (Orencia®), ``anti-IL-6 ``Pharmaceuticals such as tocilizumab (tocilizumab ) (Actemra®), diclofenac (diclofenac), cortisone, hyaluronic acid (Synvisc® or Hyalgan®), monoclonal antibodies such as tanezumab, anticoagulants such as heparin (Calcinparine® or Liquaemin®) And warfarin (Coumadin®), antidiarrheal drugs such as diphenoxylate (Lomotil®) and loperamide (Imodium®), bile acid binders such as cholestyramine, allo Alosetron (Lotronex®), lubiprostone (Amitiza®), laxatives such as milk of magnesia, polyethylene glycol (MiraLax®), Dulcolax®, Correctol® and Senokot®, anticholinergic Alkaline or antispasmodic drugs such as dicyclomine (Bentyl®), Singulair®, beta-2 agonists such as albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), oxinaline (metaproterenol) (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®) and formaldehyde Formoterol (Foradil®), anticholinergic agents such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), inhaled corticosteroids such as dipropionic acid Beclomethasone dipropionate (Beclovent®, Qvar® and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®) And flunisolide (Aerobid®), Afviar®, Symbicort®, Dulera®, cromolyn sodium (Intal®), methylxanthines such as theophylline (Theo-Dur®, Theolair®, Slo-bid®) , Uniphyl®, Theo-24®) and aminophylline, IgE antibodies such as omalizumab (omalizumab) ( Xolair®), nucleoside reverse transcriptase inhibitors such as zidovudine (Retrovir®), abacavir (Ziagen®), abacavir/lamivudine (Epzicom) ®), abacavir/lamivudine/zidovudine (Trizivir®), didanosine (Videx®), emtricitabine (Emtriva®), lamivudine (Epivir®), Lamivudine/Zidovudine (Combivir®), Stavudine (Zerit®) and Zalcitabine (Hivid®), non-nucleoside reverse transcriptase inhibitors Such as delavirdine (Rescriptor®), efavirenz (Sustiva®), nevairapine (Viramune®) and etravirine (Intelence®), nucleoside reverse transcriptase inhibition Agents such as tenofovir (Viread®), protease inhibitors such as amprenavir (Agenerase®), atazanavir (Reyataz®), darunavir (darunavir) ( Prezista®), fosamprenavir (Lexiva®), indinavir (Crixivan®), lopinavir (lopinavir) and ritonavir (Kaletra®), nelfinavir ( nelfinavir (Viracept®), ritonavir (Norvir®), saquinavir (Fortovase® or Invirase®) and tipranavir (Aptivus®), entry inhibitors such as Enfuvir Enfuvirtide (Fuzeon®) and maraviroc (Selzentry®), integrase inhibitors such as raltegravir (Isentress®), doxorubicin (Hydrodaunorubicin®), vincristine (vincristine) (Oncovin®), bortezomib (Velcade®) and a combination of dexamethasone (Decadron®) and lenalidomide (Revlimid®), or any combination thereof.

In another embodiment, the present invention provides a method for treating rheumatoid arthritis, which comprises administering a compound of formula I and one or more other therapeutic agents selected from the group consisting of non-steroidal anti-inflammatory drugs ( NSAIDS) (such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib), corticosteroids (such as prednisone, prednisolone, methylprednisolone, hydrocortisone) Pine, etc.), sulfasalazine (Azulfidine®), anti-malarial drugs such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), methotrexate (Rheumatrex®), gold salts such as gold thiodextrose (Solganal®) , Gold thiomalate (Myochrysine®) and Auranofin (Ridaura®), D-penicillamine (Depen® or Cuprimine®), azathioprine (Imuran®), Cytoxan®, Cytoxan® (Leukeran®), cyclosporine (Sandimmune®), leflunomide (Arava®) and "anti-TNF" agents such as etanercept (Enbrel®), infliximab (Remicade®), gallizumab (Simponi®), pegylated certuzumab (Cimzia®) and adalimumab (Humira®), ``anti-IL-1'' agents such as anakinra (Kineret®) and linacipr (Arcalyst®), antibodies such as rituximab (Rituxan®), "anti-T cell" agents such as abatacept (Orencia®), and "anti-IL-6" agents such as tocilizumab (Actemra®).

In some embodiments, the present invention provides a method for treating osteoarthritis, which comprises administering a compound of formula I and one or more other therapeutic agents selected from the group consisting of acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDS ) Such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®) and monoclonal antibodies such as tanibs.

In some embodiments, the present invention provides a method for treating systemic lupus erythematosus, which comprises administering a compound of formula I and one or more other therapeutic agents selected from the group consisting of acetaminophen, non-steroidal anti-inflammatory drugs ( NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, corticosteroids (such as prednisone, prednisolone, methylprednisolone, hydrocortisone) Etc.), antimalarial drugs such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), cyclophosphamide (Cytoxan®), methotrexate (Rheumatrex®), azathioprine (Imuran®) and anticoagulants Such as heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®).

In some embodiments, the present invention provides a method for treating Crohn's disease, ulcerative colitis or inflammatory bowel disease, which comprises administering a compound of formula I and one or more selected from the following to a patient in need Other therapeutic agents: mesalamine (Asacol®) sulfasalazine (Azulfidine®), antidiarrheal drugs such as diphenoxylate (Lomotil®) and loperamide (Imodium®), bile acid binders such as sodium sulfate Choleramine, Alosetron (Lotronex®), Lubiprostone (Amitiza®), laxatives such as milk of magnesia, polyethylene glycol (MiraLax®), Dulcolax®, Correctol® and Senokot® and anticholinergics Anticonvulsants or antispasmodic drugs such as dicyclic amine (Bentyl®), anti-TNF therapy, steroids, and antibiotics (such as metronidazole (Flagyl) or ciprofloxacin).

In some embodiments, the present invention provides a method for treating asthma, which comprises administering a compound of formula I and one or more other therapeutic agents selected from the group consisting of: Singulair®, β-2 agonist ( Such as salbutamol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), oxinaline (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), xinafoate Salmeterol acid (Serevent® and formoterol (Foradil®)), anticholinergic agents (such as ipratropium bromide (Atrovent®) and tiotropium bromide (Spiriva®)), inhaled corticosteroids (Such as prednisone, prednisolone, beclomethasone dipropionate (Beclovent®, Qvar® and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®) , Flunisolide (Aerobid®), Afviar®, Symbicort® and Dulera®, cromolyn sodium (Intal®)), methylxanthines (such as theophylline (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®, Theo-24®)) and aminophylline and IgE antibodies (such as omalizumab (Xolair®)).

In some embodiments, the present invention provides a method for treating COPD, which comprises administering a compound of formula I and one or more other therapeutic agents selected from the group consisting of: β-2 agonists (such as salbutamol ( Ventolin® HFA, Proventil® HFA), Levalbuterol (Xopenex®), Ocinaline (Alupent®), Pirbuterol Acetate (Maxair®), Terbutaline Sulfate (Brethaire®), Salmeter Xinafoate (Serevent® and formoterol (Foradil®)), anticholinergic agents (such as ipratropium bromide (Atrovent®) and tiotropium bromide (Spiriva®)), methylxanthines (such as tea Alkali (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®, Theo-24®) and aminophylline), inhaled corticosteroids (such as prednisone, prednisolone, beclomethasone dipropionate) (Beclovent®, Qvar® and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), flunisolide (Aerobid®), Afviar®, Symbicort® and Dulera ®).

In another embodiment, the present invention provides a method for treating hematological malignancies, which comprises administering a compound of formula I and one or more other therapeutic agents selected from the group consisting of Rituxan (Rituxan) to a patient in need thereof. ®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, hedgehog signaling inhibitor, BTK inhibitor, JAK/pan-JAK inhibitor , PI3K inhibitors, SYK inhibitors, and combinations thereof.

In another embodiment, the present invention provides a method for treating solid tumors, which comprises administering a compound of formula I and one or more other therapeutic agents selected from the group consisting of Rituxan® to patients in need thereof. ), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, hedgehog signaling inhibitor, BTK inhibitor, JAK/pan-JAK inhibitor, PI3K inhibitors, SYK inhibitors, and combinations thereof.

In another embodiment, the present invention provides a method for treating hematological malignancies, which comprises administering a compound of formula I and an inhibitor of the hedgehog (Hh) signaling pathway to a patient in need thereof. In some embodiments, the hematological malignancy is DLBCL (Ramirez et al. "Defining causative factors contributing in the activation of hedgehog signaling in diffuse large B-cell lymphoma" Leuk. Res. (2012), published online on July 17, And its full text is incorporated herein by reference).

In another embodiment, the present invention provides a method of treating diffuse large B-cell lymphoma (DLBCL), which comprises administering a compound of formula I and one or more other therapeutic agents selected from the following to a patient in need: Rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, hedgehog signaling inhibitor, and combinations thereof.

In another embodiment, the present invention provides a method of treating multiple myeloma, which comprises administering a compound of formula I and one or more other therapeutic agents selected from the group consisting of bortezomib (Velcade® ), and dexamethasone (Decadron®), hedgehog signaling inhibitor, BTK inhibitor, JAK/pan-JAK inhibitor, TYK2 inhibitor, PI3K inhibitor, SYK inhibitor and lenalidomide (Revlimid®) combination.

In another embodiment, the present invention provides a method for treating a disease or reducing its severity, which comprises administering a compound of formula I and a BTK inhibitor to a patient in need, wherein the disease is selected from inflammatory bowel disease, Arthritis, systemic lupus erythematosus (SLE), vasculitis, idiopathic thrombocytopenic purpura (ITP), rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile joints Inflammation, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis, Graves' disease, autoimmune thyroiditis, Sjogren syndrome, multiple sclerosis, systemic Sclerosis, Neuro Lyme disease, Guillain-Barre syndrome, acute disseminated cerebrospinal meningitis, Addison's disease, ocular clonus-myoclonus syndrome, ankylosing spondylitis, antiphospholipid antibodies Syndrome, aplastic anemia, autoimmune hepatitis, autoimmune gastritis, pernicious anemia, celiac disease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, Primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, warm antibody autoimmune hemolytic anemia, Wegener's granuloma, psoriasis, systemic Sudden illness, Behcet’s disease, chronic fatigue, familial autonomic abnormalities, membranous glomerulonephropathy, endometriosis, interstitial cystitis, pemphigus vulgaris, bullous pemphigoid, Neuromyotonia, scleroderma, vulvar pain, hyperproliferative disease, transplanted organ or tissue rejection, acquired immunodeficiency syndrome (AIDS, also known as HIV), type 1 diabetes, graft-versus-host disease, transplantation, infusion , Allergic reactions (anaphylaxis), allergies (for example, to plant pollen, latex, drugs, food, insect toxins, animal hair, animal dander, dust mites or cockroach calyx), type I hypersensitivity, allergic keratitis, Allergic rhinitis and atopic dermatitis, asthma, appendicitis, atopic dermatitis, asthma, allergy, blepharitis, bronchiolitis, bronchitis, mucocystitis, cervicitis, cholangitis, cholecystitis, chronic transplantation Rejection, colitis, conjunctivitis, Crohn's disease, cystitis, lacrimal gland inflammation, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymis Inflammation, fasciitis, fibrositis, gastritis, gastroenteritis, Hen-Scher's purpura, hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, spinal cord Inflammatory myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, mumps, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, pneumonia, pneumonia, polymyositis, proctitis, prostate Inflammation, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendinitis, tonsillitis, ulcerative nodules Enteritis, uveitis, vaginitis, vasculitis, or vulvitis, B-cell proliferative disease (for example, diffuse large B-cell lymphoma), follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic Leukemia, acute lymphocytic leukemia, B-cell prelymphocytic leukemia, lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia (Waldenstrom macroglobulinemia), splenic marginal zone lymphoma, multiple myeloma (also known as plasma cell Myeloma), non-Hodgkin's lymphoma, Hodgkin's lymphoma, plasmacytoma, extranodal marginal zone B-cell lymphoma, nodular marginal zone B-cell lymphoma, mantle cell lymphoma, mediastinum (thymus ) Large B-cell lymphoma, intravascular large B-cell lymphoma, primary exudative lymphoma, Burkitt lymphoma/leukemia or lymphomatoid granulomatosis, breast cancer, prostate cancer or mast cell carcinoma ( For example,'mast cell tumor, mast cell leukemia, mast cell sarcoma, systemic mast cell hyperplasia), bone cancer, colorectal cancer, pancreatic cancer, bone and joint diseases (including (but not limited to) rheumatoid arthritis), serum Negative spondyloarthritis (including ankylosing spondylitis, psoriatic arthritis and Reiter's disease), Behcet's disease, Sjogren's syndrome, systemic sclerosis, osteoporosis, bone cancer, bone metastasis, thromboembolism ( For example, myocardial infarction, angina pectoris, re-occlusion after revascularization, restenosis after revascularization, re-occlusion after aortic coronary bypass, restenosis after aortic coronary bypass, stroke, temporary ischemia, peripheral arteries Obliterative diseases, pulmonary embolism, deep vein thrombosis), pelvic inflammatory diseases, urethritis, skin sunburn, sinusitis, pneumonia, encephalitis, meningitis, myocarditis, nephritis, osteomyelitis, myositis, hepatitis, gastritis, Enteritis, dermatitis, gingivitis, appendicitis, pancreatitis, cholecystitis, gamma globulin deficiency, psoriasis, allergy, Crohn's disease, irritable bowel syndrome, ulcerative colitis, Sjogren syndrome, tissue transplant rejection, Hyperacute rejection of transplanted organs, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), autoimmune polyglandular disease (also called autoimmune polyglandular disease), autoimmune alopecia, pernicious anemia , Glomerulonephritis, dermatomyositis, multiple sclerosis, scleroderma, vasculitis, autoimmune hemolysis and thrombocytopenia, Goodpast syndrome, atherosclerosis, Addison's disease, Parkinson's disease, Alzheimer's disease, diabetes, septic shock, systemic lupus erythematosus (SLE), rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, osteoarthritis, chronic idiopathic platelets Reduced purpura, Waldenstrom's macroglobulinemia, myasthenia gravis, Hashimoto's thyroiditis, atopic dermatitis, degenerative joint disease, vitiligo, autoimmune hypopituitarism, Guillain-Barre syndrome, Behcet's disease , Scleroderma, Mycosis Fungoides, Acute Inflammatory Reactions (such as Acute Respiratory Distress Syndrome and Ischemia/Reperfusion Injury) and Gr's Disease.

In another embodiment, the present invention provides a method for treating a disease or reducing its severity, which comprises administering a compound of formula I and a PI3K inhibitor to a patient in need, wherein the disease is selected from cancer, neurodegenerative Diseases, angiogenesis disorders, viral diseases, autoimmune diseases, inflammatory diseases, hormone-related diseases, conditions related to organ transplantation, immunodeficiency, destructive bone diseases, proliferative diseases, infectious diseases, and cell death related The pathological conditions, thrombin-induced platelet aggregation, chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), liver disease, pathological immune conditions involving T cell activation, cardiovascular disorders, and CNS disorders.

In another embodiment, the present invention provides a method for treating a disease or reducing its severity, which comprises administering a compound of formula I and a PI3K inhibitor to a patient in need thereof, wherein the disease is selected from brain, kidney (for example, , Renal cell carcinoma (RCC)), liver, adrenal gland, bladder, breast, stomach, stomach tumor, ovary, colon, rectum, prostate, pancreas, lung, vagina, endometrium, cervix, testis, genitourinary tract, esophagus , Benign or malignant tumors of throat, skin, bone or thyroid, cancer or solid tumor, sarcoma, glioblastoma, neuroblastoma, multiple myeloma or gastrointestinal cancer, especially colon cancer or colorectal adenoma or Head and neck tumors, epidermal hyperplasia, psoriasis, prostate hyperplasia, neoplasia, epithelioma formation, adenoma, malignant adenoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer, lymphoma (including, for example, non-small cell lung cancer) Hodgkin's lymphoma (NHL) and Hodgkin's lymphoma (also known as Hodgkin's or Hodgkin's disease), breast cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma , Seminoma, melanoma or leukemia, diseases include Cowden syndrome, Lhermitte-Dudos disease and Bannayan-Zonana syndrome or among them Diseases with abnormal activation of the PI3K/PKB pathway, asthma of any type or origin (including endogenous (non-allergic) asthma and exogenous (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchial asthma, Exercise-induced asthma, occupational asthma and asthma induced after bacterial infection), acute lung injury (ALI), adult/acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary (pulmonary), airway or lung disease ( COPD, COAD or COLD) (including chronic bronchitis or related dyspnea, emphysema, and deterioration of airway hyperresponsiveness caused by other drug therapies (specifically, other inhaled drug therapies)), any type and origin Bronchitis (including but not limited to acute, peanut inhalation (arachidic), catarrhal, Croupus, chronic or tuberculous bronchitis), pneumoconiosis of any type or origin (a type of lung Inflammatory (usually occupational) diseases, often accompanied by airway blockage (chronic or acute) and caused by repeated inhalation of dust) (including but not limited to) such as bauxite lung, coal lung disease, asbestos lung, stone end lung, ostrich Pneumoconiosis, iron pneumoconiosis, silicosis, smoke pneumoconiosis and cotton pneumoconiosis), Loffler's syndrome pneumonia, eosinophils, pneumonia, parasites (specified metazoans) infections (including tropical eosinophils) Hyperplasia), bronchopulmonary aspergillosis, polyarteritis nodosa (including allergic-granulomatosis (Churg-Strauss) syndrome), eosinophilic granuloma and occasionally caused by drug reactions that affect airway eosinophils- Related diseases, cowhide Ringworm, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, herpetiform dermatitis, scleroderma, vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigoid , Lupus erythematosus, pemphigus, acquired bullous epidermal laxity, conjunctivitis, keratoconjunctivitis sicca and vernal conjunctivitis, diseases that affect the nose (including allergic rhinitis) and those involving autoimmune reactions or having autoimmune components Or cause inflammatory diseases, including autoimmune hematological disorders (such as hemolytic anemia, aplastic anemia, pure red cell anemia and idiopathic thrombocytopenia), systemic lupus erythematosus, rheumatoid arthritis, Polychondritis, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Stefan-Johnson syndrome, idiopathic steatorrhea, autoimmune inflammatory bowel disease (e.g. Ulcerative colitis and Crohn’s disease), endocrine eye disease, Graves’ disease, sarcoidosis, alveolar inflammation, chronic allergic pneumonia, multiple sclerosis, primary biliary cirrhosis, grapevine Meningitis (anterior and posterior), keratoconjunctivitis sicca and vernal keratoconjunctivitis, pulmonary interstitial fibrosis, psoriatic arthritis, and glomerulonephritis (with and without renal syndromes, such as primary renal syndromes or micro Pathological nephropathy, restenosis, cardiac hypertrophy, atherosclerosis, myocardial infarction, ischemic stroke and congestive heart failure), Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington Huntington's disease and cerebral ischemia, and neurodegenerative diseases caused by trauma, glutamine neurotoxicity and hypoxia.

In some embodiments, the present invention provides a method for treating a disease or reducing its severity, which comprises administering a compound of formula I and a Bcl-2 inhibitor to a patient in need, wherein the disease is an inflammatory disease, autologous Immune diseases, proliferative diseases, endocrine diseases, neurological diseases or transplant-related diseases. In some embodiments, the condition is a proliferative disease, lupus or lupus nephritis. In some embodiments, the proliferative disease is chronic lymphocytic leukemia, diffuse large B-cell lymphoma, Hodgkin's disease, small cell lung cancer, non-small cell lung cancer, myelodysplastic syndrome, lymphoma, hematological tumors Or solid tumors.

According to the method of the present invention, the compounds and compositions can be administered in any amount and any route of administration that can effectively treat or reduce the severity of the following diseases: autoimmune diseases, inflammatory diseases, proliferative diseases, endocrine diseases, neurological diseases, or Diseases related to transplantation. The exact amount required will vary from individual to individual, depending on the individual's race, age and general condition, the severity of the infection, the specific agent, its mode of administration, and so on. Preferably, the compound of the present invention is formulated into a dosage unit form for ease of administration and uniformity of dosage. The expression "dosage unit form" as used herein refers to a physically discrete unit of medicament suitable for the patient to be treated. However, it should be understood that the total daily dosage of the compounds and compositions of the present invention will be determined by the attending physician in a reasonable range of medical judgment. Specific effective amount of water for any specific patient or organism The level will depend on various factors, including the condition being treated and the severity of the condition; the activity of the specific compound used; the specific composition, age, weight, general health, gender, and diet used by the patient; the specific Compound administration time, route of administration and excretion rate; duration of treatment; drugs used in combination with or concurrently with the specific compound used; and similar factors well known in medical technology. As used herein, the term "patient" means an animal, preferably a mammal, and most preferably a human.

The pharmaceutically acceptable composition of the present invention can be oral, rectal, parenteral, intracisternal, intravaginal, intraperitoneal, topical (such as by powder, ointment or drops), or buccal , As an oral or nasal spray to humans and other animals, depending on the severity of the infection to be treated. In certain embodiments, the compound of the present invention can be administered orally or parenterally, once a day or more Times to obtain the desired curative effect.

Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compound, the liquid dosage form may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, Benzyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide, oil (specifically, cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerin, Fatty acid esters of tetrahydrofuranol, polyethylene glycol, sorbitol anhydride and mixtures thereof. In addition to inert diluents, oral compositions may also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, and perfuming agents.

Injectable preparations (for example, sterile injectable aqueous or oily suspensions) can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. also, Sterile fixed oils are usually used as solvents or suspending media. For this purpose, any non-irritating fixed oil can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injections.

The injectable formulations can be sterilized, for example, by filtering through a bacteria-retaining filter, or incorporating sterilizing agents into the form of sterile solid compositions, which can be dissolved or dispersed in sterile water or other sterile materials before use. In the injection medium.

In order to prolong the effect of the compound of the present invention, it is usually necessary to slow the absorption of the compound from subcutaneous or intramuscular injections. This can be achieved by using a liquid suspension of poorly water-soluble crystalline or amorphous materials. The absorption rate of a compound depends on its dissolution rate, which in turn can depend on the crystal size and crystal shape. Alternatively, delayed absorption of the compound form by parenteral administration is achieved by dissolving or suspending the compound in an oily vehicle. The injectable depot form is by forming a microencapsulated matrix of the compound in a biodegradable polymer such as polylactide-polyglycolide. According to the ratio of compound to polymer and the properties of the specific polymer used, the release rate of the compound can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by trapping the compound in liposomes or microemulsions that are compatible with body tissues.

The composition for rectal or vaginal administration is preferably a suppository, which can be prepared by mixing the compound of the present invention with a suitable non-irritating compound that is solid at ambient temperature but liquid at body temperature and therefore melts in the rectum or vaginal cavity and releases the active compound. It is prepared by mixing sexual excipients or carriers (such as cocoa butter, polyethylene glycol or suppository wax).

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one inert pharmaceutically acceptable excipient or carrier (such as sodium citrate or dicalcium phosphate) and/or a) filler or extender ( Such as starch, lactose, sucrose, glucose, mannitol and silicic acid), b) binders (such as, for example, carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic), c) Humectants (such as glycerin), d) disintegrants (agar-agar, carbonic acid Calcium, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate), e) solution blockers (such as paraffin), f) absorption enhancers (such as quaternary ammonium compounds), g) wetting Agents (such as cetyl alcohol and glyceryl monostearate), h) adsorbents (such as kaolin and bentonite) and i) lubricants (such as talc, calcium stearate, magnesium stearate, solid poly Ethylene glycol, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also contain buffering agents.

Similar types of solid compositions can also be used as fillers in soft and hard filled gelatin capsules, which use excipients such as lactose/milk sugar and high molecular weight polyethylene glycol. The solid dosage forms of tablets, dragees, capsules, pills, and granules may have coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation technology. It may optionally include a sunscreen agent, and may also be a composition that releases the active ingredient in a certain part of the intestinal tract in a delayed manner only or preferably, as appropriate. Examples of embedding compositions that can be used include polymeric substances and waxes. Similar types of solid compositions can also be used as fillers in soft and hard filled gelatin capsules, which use excipients such as lactose/milk sugar and high molecular weight polyethylene glycol.

The active compound may also be in the form of microcapsules with one or more excipients as described above. The solid dosage forms of tablets, dragees, capsules, pills, and granules may have coatings and shells, such as enteric coatings, controlled release coatings, and other coatings well known in the pharmaceutical formulation technology. In these solid dosage forms, the active compound may be mixed with at least one inert diluent such as sucrose, lactose or starch. As a common practice, these dosage forms may also contain other substances besides inert diluents, such as tablet pressing lubricants and other tablet pressing aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage form may also contain buffering agents. It may optionally include a sunscreen agent, and may also be a composition that releases the active ingredient in a certain part of the intestinal tract in a delayed manner only or preferably, as appropriate. Examples of embedding compositions that can be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration include ointments, pastes, creams, lotions, Gels, powders, solutions, sprays, inhalants or patches. The active ingredient is mixed with pharmaceutically acceptable carriers and any necessary preservatives or buffers that may be required under sterile conditions. Ophthalmic formulations, ear drops and eye drops are also included in the scope of the present invention. In addition, the present invention encompasses the use of transdermal patches, which have the additional advantage of controlled delivery of the compound to the body. These dosage forms can be prepared by dissolving or dispersing the compound in an appropriate medium. Absorption enhancers can also be used to increase the flux of the compound through the skin. The rate can be controlled by providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

According to one embodiment, the present invention relates to a method for inhibiting protein kinase activity in a biological sample, which includes the step of contacting the biological sample with a compound of the present invention or a composition containing the compound.

According to another embodiment, the present invention relates to a method for inhibiting the activity of TYK2 or a mutant thereof in a biological sample, which includes the step of contacting the biological sample with the compound of the present invention or a composition containing the compound. In some embodiments, the present invention relates to a method for reversibly inhibiting the activity of TYK2 or a mutant thereof in a biological sample, which includes the step of contacting the biological sample with the compound of the present invention or a composition containing the compound.

In another embodiment, the present invention provides a method for selectively inhibiting TYK2 relative to one or more of JAK1, JAK2, and JAK3. In some embodiments, the compounds of the present invention are more than 2-fold selective for JAK1/2/3. In some embodiments, the compounds of the present invention are more than 5-fold selective for JAK1/2/3. In some embodiments, the compounds of the present invention are more than 10-fold selective for JAK1/2/3. In some embodiments, the compounds of the present invention are more than 50-fold selective for JAK1/2/3. In some embodiments, the compounds of the present invention are more than 100-fold selective for JAK1/2/3.

The term "biological sample" as used herein includes (but is not limited to) cell culture or extracts thereof; biopsy materials obtained from mammals or extracts thereof; and blood, saliva, urine, feces, semen, Tears or other body fluids or extracts thereof.

Inhibiting the activity of TYK2 (or its mutants) in biological samples can be used by those who are familiar with this technology Known various purposes. Examples of such purposes include, but are not limited to, blood transfusion, organ transplantation, biological specimen storage, and biological analysis.

Another embodiment of the present invention relates to a method for inhibiting protein kinase activity in a patient, which includes the step of administering a compound of the present invention or a composition containing the compound to the patient.

According to another embodiment, the present invention relates to a method for inhibiting the activity of TYK2 or a mutant thereof in a patient, which comprises the step of administering a compound of the present invention or a composition containing the compound to the patient. According to certain embodiments, the present invention relates to a method for reversibly inhibiting the activity of one or more of TYK2 or its mutants in a patient, which comprises the step of administering a compound of the present invention or a composition containing the compound to the patient . In other embodiments, the present invention provides a method for treating a condition mediated by TYK2 or its mutants in a patient in need thereof, which comprises administering to the patient a compound of the present invention or a pharmaceutically acceptable composition thereof step. This article describes these conditions in detail.

Depending on the specific condition or disease to be treated, other therapeutic agents usually administered to treat the condition may also be present in the composition of the present invention. As used herein, other therapeutic agents that are usually administered to treat a particular disease or condition are considered "applicable to the disease or condition being treated."

The composition of the present invention can also be used advantageously in combination with other therapeutic agents. In some embodiments, the other therapeutic compound is an anti-proliferative compound. Such anti-proliferative compounds include (but are not limited to) aromatase inhibitors; anti-estrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule active compounds; alkylated compounds; histone deacetylation Enzyme inhibitors; compounds that induce cell differentiation; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; anti-tumor anti-metabolites; platinum compounds; compounds that target/reduce protein or lipid kinase activity and other anti- Angiogenesis compounds; compounds that target, decrease or inhibit the activity of protein or lipid phosphatase; gonadal agonists; antiandrogens; methionine aminopeptidase inhibitors; matrix metalloproteinase inhibitors; bisphosphonates ; Biological response modifiers; Anti-proliferative antibodies; Heparanase inhibitors; Ras carcinogenic isoforms inhibitors; Telomerase inhibitors; Proteasome inhibitors; Compounds for the treatment of hematological malignancies; Targeting , Compounds that reduce or inhibit the activity of Flt-3; Hsp90 inhibitors, such as 17-AAG (17-allylaminogeldanamycin (allylaminogeldanamycin), NSC330507), 17-DMAG (17-dimethylaminoethyl) Amino-17-demethoxy-geldanamycin, NSC707545), IPI-504, CNF1010, CNF2024, CNF1010 from Conforma Therapeutics; temozolomide (Temodal ^® ); spindle kinesin inhibitors such as SB715992 or SB743921 from GlaxoSmithKline, or pentamidine/chlorpromazine from CombinatoRx; MEK inhibitors, such as ARRY142886 from Array BioPharma, AZD6244 from AstraZeneca, PD181461 and leucovorin from Pfizer. As used herein, the term "aromatase inhibitor" refers to compounds that inhibit the production of estrogen (for example, the conversion of substrates androstenedione and testosterone to estrone and estradiol, respectively). The term includes (but is not limited to) steroids (especially atamestane, exemestane and formestane) and specifically non-steroids (especially aminoglutethimide) , Roglethimide, pyridoglutethimide, trilostane, testolactone, ketoconazole, vorozole, fadrozole, anastrozole (anastrozole) and letrozole (letrozole). exemestane under the brand name Aromasin ^TM system sales. Formestane Department under the brand name Lentaron ^TM sales. letrozole-line under the brand name Afema ^TM sales. anastrozole It is sold under the brand name Arimidex ^TM . Letrozole is sold under the brand name Femara ^TM or Femar ^TM . Aluminamide is sold under the brand name Orimeten ^TM . The composition of the present invention containing a chemotherapeutic agent (which is an aromatase inhibitor) It is particularly useful for treating hormone receptor-positive tumors, such as breast tumors.

As used in the text, the term "antiestrogens" refers to compounds that antagonize the effects of estrogen at the estrogen receptor level. The term includes (but is not limited to) tamoxifen, fulvestrant, raloxifene, and raloxifene hydrochloride. Tamoxifen is sold under the brand name Nolvadex ^™ . Raloxifene hydrochloride is sold under the trade name Evista ^™ . Fluvistran can be administered under the ^{brand name Faslodex™.} The combination of the invention comprising a chemotherapeutic agent (which is an anti-estrogens) is particularly useful for the treatment of estrogen receptor positive tumors, such as breast tumors.

The term "anti-androgen" as used herein refers to any substance that can inhibit the biological effects of androgens, and includes (but is not limited to) bicalutamide (Casodex ^™ ). As used herein, the term "gonad release agonist" includes, but is not limited to, abarelix, goserelin, and goserelin acetate. Goserelin can be administered under the ^{trade name Zoladex TM.}

As used herein, the term "topoisomerase I inhibitor" includes (but is not limited to) topotecan, gimatecan, irinotecan, camptothecin, and Its analogue, 9-nitrocamptothecin and macromolecular camptothecin conjugate PNU-166148. Irinotecan can be administered, for example, in the form it is sold under the ^{brand name Camptosar™.} Topotecan is sold under the brand name Hycamptin ^™ .

As used herein, the term "topoisomerase II inhibitor" includes (but is not limited to) anthracyclines, such as doxorubicin (including liposome formulations such as Caelyx ^™ ), daunorubicin , Epirubicin, idarubicin and nemorubicin; anthraquinones: mitoxantrone and losoxantrone; and podophyllin: etopo Etoposide and teniposide. Etoposide is sold under the trade name Etopophos ^(TM) . Teniposide is sold under the trade name VM 26-Bristol. Doxorubicin is sold under the trade name Acriblastin ^™ or Adriamycin ^™ . The epirubic galaxy is sold under the trade name Farmorubicin ^(TM) . The Idaby Galaxy is sold under the trade name Zavedos ^TM . Mitoxantrone is sold under the brand name Novantron.

The term "microtubule active agent" refers to microtubule stabilizing compounds, microtubule destabilizing compounds, and microtubule polymerization inhibitors, including but not limited to taxanes such as paclitaxel and docetaxel ); Vinca alkaloids, such as vinblastine (vinblastine) or vinblastine sulfate, vincristine or vincristine sulfate and vinorelbine (vinorelbine); disc-shaped Demolide (discodermolides); colchicine (cochicine) ) And epothilones and their derivatives. Paclitaxel is sold under the trade name Taxol ^™ . Docetaxel is sold under the trade name Taxotere ^TM. Vinblastine sulfate is sold under the trade name Vinblastin RP ^™ . Vincristine sulfate is sold under the trade name Farmistin ^TM .

The term "alkylating agent" as used herein includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan, or nitrosourea (BCNU or Gliadel). Cyclophosphamide is sold under the trade name Cyclostin ^™. Ififosfamide is sold under the brand name Holoxan ^(TM).

The term "histone deacetylase inhibitor" or "HDAC inhibitor" refers to a compound that inhibits histone deacetylase and has anti-proliferative properties. This includes, but is not limited to, suberylaniline hydroxamic acid (SAHA).

The term "anti-tumor anti-metabolite" includes (but is not limited to) 5-fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylation compounds (such as 5-azacytidine and Decitabine (decitabine), methotrexate and edatrexate and folate antagonists (such as pemetrexed). Capecitabine is sold under the trade name Xeloda ^TM . Gemcitabine is sold under the brand name Gemzar ^TM .

As used herein, the term "platinum compound" includes (but is not limited to) carboplatin (carboplatin), cisplatin (cis-platin, cisplatinum), and oxaliplatin (oxaliplatin). Carboplatin can be administered, for example, in the form it is sold under the ^{brand name Carboplat™.} Oxaliplatin can be administered, for example, in the form it is sold under the ^{brand name Eloxatin™.}

The term "targeting/reducing protein or lipid kinase activity; or protein or lipid phosphatase activity; or other anti-angiogenic compounds" as used herein includes (but is not limited to) protein tyrosine kinase and/or seramine Acid and/or threonine kinase inhibitors or lipid kinase inhibitors, such as a) compounds that target, reduce or inhibit the activity of platelet-derived growth factor receptor (PDGFR), such as those that target, reduce or inhibit the activity of PDGFR Compounds, especially compounds that inhibit PDGF receptors, such as N-phenyl-2-pyrimidine-amine derivatives, such as imatinib, SU101, SU6668 and GFB-111; b) target, reduce or inhibit fiber Compounds that target, reduce or inhibit the activity of the blastogen growth factor receptor (FGFR); c) compounds that target, reduce or inhibit the activity of insulin-like growth factor receptor I (IGF-IR), such as target, reduce or inhibit the activity of IGF-IR The compound, especially a compound that inhibits the kinase activity of IGF-I receptor, or an antibody that targets the extracellular domain of IGF-I receptor or its growth factor; d) targets, reduces or inhibits Trk receptor tyramine Acid kinase family compounds or ephrin B4 inhibitors; e) compounds targeting, reducing or inhibiting the activity of the AxI receptor tyrosine kinase family; f) targeting, reducing or inhibiting the Ret receptor tyrosine kinase Active compounds; g) compounds that target, reduce or inhibit the activity of Kit/SCFR receptor tyrosine kinase, such as imatinib; h) target, reduce or inhibit C-kit receptor tyrosine kinase (its A compound that is part of the PDGFR family) activity, such as a compound that targets, reduces or inhibits the activity of the c-Kit receptor tyrosine kinase family, especially a compound that inhibits the activity of the c-Kit receptor, such as imatinib I) Targeting, reducing or inhibiting the activity of c-Abl family members, their gene fusion products (such as BCR-Abl kinase) and mutants, such as targeting, reducing or inhibiting c-Abl family members and their gene fusions Active compounds of the product, such as N-phenyl-2-pyrimidine-amine derivatives, such as imatinib or nilotinib (AMN107); PD180970; AG957; NSC 680410; PD173955 from ParkeDavis; or Dasatinib (BMS-354825); j) Targets, reduces or inhibits protein kinase C (PKC) and Raf serine/threonine kinase family members, MEK, SRC, JAK/pan-JAK, FAK , PDK1, PKB/Akt, Ras/MAPK, PI3K, SYK, BTK and TEC family members, and/or cyclin-dependent kinase family (CDK) members of the active compounds, including staurosporine derivatives , Such as midostau rin); Examples of other compounds include UCN-01, safingol, BAY 43-9006, Bryostatin 1, Perifosine; Imofosine; RO 318220 And RO 320432; GO 6976; lsis 3521; LY333531/LY379196; isoquinoline compounds; FTIs; PD184352 or QAN697 (P13K inhibitor) or AT7519 (CDK inhibitor); k) Targeting, reducing or inhibiting protein tyrosine kinase Compounds that inhibit activity, such as compounds that target, decrease or inhibit the activity of protein tyrosine kinase inhibitors include imatinib mesylate (Gleevec ^TM ) or tyrosine phosphorylation inhibitors (tyrphostin), such as tyrosine Phosphorylation inhibitor A23/RG-50810; AG 99; Tyrosine phosphorylation inhibitor AG 213; Tyrosine phosphorylation inhibitor AG 1748; Tyrosine phosphorylation inhibitor AG 490; Tyrosine phosphorylation inhibitor B44; tyrosine phosphorylation inhibitor B44(+) enantiomer; tyrosine phosphorylation inhibitor AG 555; AG 494; tyrosine phosphorylation inhibitor AG 556, AG957 and adaphostin (4-{[(2,5-Dihydroxyphenyl)methyl]amino}-adamantyl benzoate; NSC 680410, adafotine); 1) Targeting, reducing or inhibiting receptor tyrosine epidermal growth factor kinase family (the form of homodimers or heterodimers with _{EGFR 1, ErbB2, ErbB3, ErbB4} ) and a compound of the mutation activity, such as targeting, decreasing or inhibiting the activity of the epidermal growth factor family of receptor inhibition Especially compounds, proteins or antibodies that inhibit EGF receptor tyrosine kinase family members (EGF receptor, ErbB2, ErbB3 and ErbB4) or bind EGF or EGF-related ligands, CP 358774, ZD 1839, ZM 105180; Trastuzumab monoclonal antibody (trastuzumab) (Herceptin ^TM), cetuximab (cetuximab) (Erbitux ^TM), gefitinib (Iressa), Tarceva (Tarceva), OSI-774, Cl-1033, EKB-569, GW -2016, E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 or E7.6.3 and 7H-pyrrolo-[2,3-d]pyrimidine derivatives ; M) Compounds that target, reduce or inhibit the activity of c-Met receptors, such as compounds that target, reduce or inhibit the activity of c-Met, especially compounds that inhibit the kinase activity of c-Met receptors or target c-Met The extracellular domain or HGF-binding anti N) Compounds that target, reduce or inhibit the kinase activity of one or more JAK family members (JAK1/JAK2/JAK3/TYK2 and pan-JAK), including (but not limited to) PRT-062070, SB-1578, Pakistan Baricitinib, pacritinib, momelotinib, VX-509, AZD-1480, TG-101348, tofacitinib and ruxolitinib; o) Compounds that target, decrease or inhibit the kinase activity of PI3 kinase (PI3K), including (but not limited to) ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, Bupani Buparlisib, pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765 and idelalisib; and q) targeting , Compounds that reduce or inhibit the signal transmission effect of the hedgehog protein (Hh) or SMO receptor (SMO) pathway, including (but not limited to) cyclopamine, vismodegib, and itraconazole ( itraconazole), erismodegib and IPI-926 (saridegib).

The term "PI3K inhibitor" as used herein includes (but is not limited to) compounds having inhibitory activity against one or more enzymes in the phosphoinositide-3-kinase family, including (but not limited to) PI3Kα, PI3Kγ, PI3Kδ , PI3Kβ, PI3K-C2α, PI3K-C2β, PI3K-C2γ, Vps34, p110-α, p110-β, p110-γ, p110-δ, p85-α, p85-β, p55-γ, p150, p101 and p87 . Examples of PI3K inhibitors that can be used in the present invention include (but are not limited to) ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, Bupanisi, Pitnixi , PF-4691502, BYL-719, Dakenisi, XL-147, XL-765 and Edenicis.

The term "BTK inhibitor" as used herein includes (but is not limited to) compounds with inhibitory activity against Bruton's tyrosine kinase (BTK), including (but not limited to) AVL-292 and Rutinib (ibrutinib).

The term "SYK inhibitor" as used herein includes (but is not limited to) compounds with inhibitory activity against spleen tyrosine kinase (SYK), including (but not limited to) PRT-062070, R-343, R-333 , Excellair, PRT-062607 and fostamatinib.

The term "Bcl-2 inhibitor" as used herein includes (but is not limited to) compounds with inhibitory activity against B-cell lymphoma 2 protein (Bcl-2), including (but not limited to) ABT-199, ABT -731, ABT-737, apogossypol, Ascenta's pan-Bcl-2 inhibitor, curcumin (and its analogues), dual Bcl-2/Bcl-xL inhibitor (Infinity Pharmaceuticals /Novartis Pharmaceuticals), Genasense (G3139), HA14-1 (and its analogs; see WO2008118802), navitoclax (and its analogs, see US7390799), NH-1 (Shenayng Pharmaceutical University), obatoclax (and its analogs, see WO2004106328), S-001 (Gloria Pharmaceuticals), TW series of compounds (Univ. of Michigan), and venetoclax. In some embodiments, the Bcl-2 inhibitor is a small molecule therapeutic agent. In some embodiments, the Bcl-2 inhibitor is a small molecule peptide mimic.

Other examples of BTK inhibitory compounds and conditions that can be treated by the combination of these compounds and the compounds of the present invention can be found in WO2008039218 and WO2011090760, the entire contents of which are incorporated herein by reference.

Other examples of SYK inhibitory compounds and conditions that can be treated by the combination of these compounds and the compounds of the present invention can be found in WO2003063794, WO2005007623 and WO2006078846, the entire contents of which are incorporated herein by reference.

Other examples of PI3K inhibitory compounds and conditions that can be treated by the combination of such compounds and the compounds of the present invention can be found in WO2004019973, WO2004089925, WO2007016176, US8138347, WO2002088112, WO2007084786, WO2007129161, WO2006122806, WO2005113554, and WO2007044729, all of which Incorporated into this article by reference.

Other examples of JAK inhibitory compounds and conditions that can be treated by the combination of these compounds and the compounds of the present invention can be found in WO2009114512, WO2008109943, WO2007053452, WO2000142246 and WO2007070514, the entire contents of which are based on The way of reference is incorporated into this article.

Other anti-angiogenic compounds include compounds that have another mechanism for their activity (eg, not related to protein or lipid kinase inhibition), such as thalidomide (Thalomid ^™ ) and TNP-470.

Examples of proteasome inhibitors that can be used in combination with the compounds of the present invention include (but are not limited to) bortezomib, disulfiram, epigallocatechin (epigallocatechin)-3-gallate ( EGCG), salinosporamide A, carfilzomib, ONX-0912, CEP-18770 and MLN9708.

Compounds that target, decrease or inhibit the activity of protein or lipid phosphatase are, for example, inhibitors of phosphatase 1, phosphatase 2A or CDC25, such as okadaic acid or its derivatives.

Compounds that induce the process of cell differentiation include (but are not limited to) retinoic acid, α-, γ- or δ-tocopherol or α-, γ- or δ-tocotrienol.

The term cyclooxygenase inhibitor as used herein includes, but is not limited to, Cox-2 inhibitors, 5-alkyl substituted 2-arylaminophenyl acetic acid and derivatives, such as celecoxib (Celebrex ^TM ), rofecoxib (Vioxx ^TM ), etoricoxib, valdecoxib or 5-alkyl-2-arylaminophenyl acetic acid (such as 5-methyl-2- (2'-chloro-6'-fluoroanilino)phenylacetic acid, lumiracoxib).

As used herein, the term "bisphosphonates" includes (but is not limited to) etridonic acid, clodronic acid, tiludronic acid, pamidronic acid, Alendronic acid, ibandronic acid, risedronic acid and zoledronic acid. Etidronic acid is sold under the brand name Didronel ^™ . Clodronic acid is sold under the trade name Bonefos ^(TM) . Tiludronic acid is sold under the brand name Skelid ^™ . Pamidronic acid is sold under the brand name Aredia ^™ . Alendronic acid is sold under the trade name Fosamax ^™ . Ibandronic acid is sold under the trade name Bondranat ^TM . Risedronic acid is sold under the trade name Actonel ^™ . Zoledronic acid is sold under the trade name Zometa ^™ . The term "mTOR inhibitor" refers to compounds that inhibit mammalian target rapamycin (mTOR) and have antiproliferative properties, such as sirolimus (Rapamune®), everolimus (Certican ^TM ), CCI-779 and ABT578.

The term "heparanase inhibitor" as used herein refers to a compound that targets, reduces or inhibits the degradation of heparin sulfate. The term includes (but is not limited to) PI-88. The term "biological response modifier" as used herein refers to lymphokine or interferon.

As used herein, the term "inhibitor of Ras carcinogenic isoforms" (such as H-Ras, K-Ras, or N-Ras) refers to compounds that target, reduce or inhibit the carcinogenic activity of Ras; for example, "Farnes Base transferase inhibitors", such as L-744832, DK8G557 or R115777 (Zarnestra ^TM ). The term "telomerase inhibitor" as used herein refers to compounds that target, decrease or inhibit the activity of telomerase. Compounds that target, decrease or inhibit telomerase activity are particularly compounds that inhibit telomerase receptors, such as telomestatin.

The term "methionine peptidase inhibitor" as used herein refers to a compound that targets, reduces or inhibits the activity of methionine peptidase. Compounds that target, decrease or inhibit the activity of methionine aminopeptidase include (but are not limited to) bengamide or its derivatives.

The term "proteasome inhibitor" as used herein refers to a compound that targets, reduces or inhibits the activity of the proteasome. Compounds that target, decrease or inhibit the activity of the proteasome include, but are not limited to, bortezomib (Velcade ^™ ) and MLN 341.

The term "matrix metalloproteinase inhibitor" or ("MMP" inhibitor) as used herein includes (but is not limited to) collagen peptide mimics and non-peptide mimics inhibitors, tetracycline derivatives, such as hydrogen glycine ester peptide mimics Inhibitor batimastat and its oral bioavailability analogue marimastat (BB-2516), pumastat (prinomastat) (AG3340), metastat (NSC 683551) BMS-279251, BAY 12-9566, TAA211, MMI270B or AAJ996.

The term "compounds for the treatment of hematological malignancies" as used herein includes, but is not limited to, FMS-like tyrosine inhibitors, which target, decrease or inhibit FMS-like tyrosine receptors (Flt- 3R) active compounds; interferon, 1-β-D-arabinofuranocytosine (ara-c) and busulfan (bisulfan); ALK inhibitors, which target, reduce or inhibit anaplastic lymphoma Kinase compounds and Bcl-2 inhibitors.

Compounds that target, decrease or inhibit the activity of FMS-like tyrosine receptor (Flt-3R) are especially compounds, proteins or antibodies that inhibit members of the Flt-3R receptor kinase family, such as PKC412, midostauline, star Sporin derivatives, SU11248 and MLN518.

The term "HSP90 inhibitor" as used herein includes, but is not limited to, compounds that target, reduce or inhibit the intrinsic ATPase activity of HSP90; compounds that degrade, target, reduce or inhibit HSP90 client proteins via the ubiquitin proteasome pathway. Compounds that target, reduce or inhibit the intrinsic ATPase activity of HSP90 are especially compounds that inhibit the ATPase activity of HSP90, such as 17-allylamino, 17-demethoxygeldanamycin (17AAG) (a kind of Geldanamycin derivatives); other geldanamycin-related compounds; radicicol and HDAC inhibitors.

The term "anti-proliferative antibody" as used herein includes (but is not limited to) trastuzumab (Herceptin ^TM ), trastuzumab-DM1, erlotinib, bevacizumab (Avastin ^TM ), Tuximab (Rituxan ^® ), PRO64553 (anti-CD40) and 2C4 antibodies. The so-called antibody means a monoclonal antibody, a multi-strain antibody, a multispecific antibody formed from at least two intact antibodies, and an antibody fragment, as long as it exhibits the desired biological activity.

To treat acute myeloid leukemia (AML), the compounds of the present invention can be used in combination with standard leukemia therapies (particularly in combination with therapies used to treat AML). Specifically, the compounds of the present invention can be combined with (for example) farnesyltransferase inhibitors and/or other drugs that can be used to treat AML (such as daunorubicin, adriamycin (Adriamycin), Ara-C, VP-16). , Teniposide, Mitoxantrone, idarubicin, carboplatinum and PKC412) were administered in combination. In some embodiments, the present invention provides a method of treating AML associated with ITD and/or D835Y mutations, which comprises administering a compound of the present invention and one or more TLT3 inhibitors together. In some embodiments, the FLT3 inhibitor is selected from the group consisting of quizartinib (AC220), staurosporine derivatives (e.g. midostauline or lestautinib), sorafenib ( sorafenib), tandutinib, LY-2401401, LS-104, EB-10, famitinib, NOV-110302, NMS-P948, AST-487, G-749, SB-1317 , S-209, SC-110219, AKN-028, Fedratinib, Tozasertib and Sunitinib. In some embodiments, the FLT3 inhibitor is selected from quezatinib, midostatin, letatinib, sorafenib, and sunitinib.

Other anti-leukemia compounds include, for example, Ara-C, a pyrimidine analogue, which is a 2'-α-hydroxyribose (arabinoside) derivative of deoxycytidine. Also includes purine analogs of hypoxanthine, 6-mercaptopurine (6-MP) and fludarabine phosphate. Compounds that target, decrease or inhibit histone deacetylase (HDAC) inhibitors (such as sodium butyrate and suberylaniline hydroxamic acid (SAHA)) inhibit one of the enzymes called histone deacetylases. Enzyme activity. Specific HDAC inhibitors include MS275, SAHA, FK228 (formerly FR901228), Trichostatin A and compounds disclosed in US 6,552,065, including (but not limited to) N-hydroxy-3-[4-[[ [2-(2-Methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide or its pharmaceutically acceptable salt and N -Hydroxy-3-[4-[(2-hydroxyethyl){2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide Or its pharmaceutically acceptable salt, especially lactate. Somatostatin receptor antagonists as used herein refer to compounds that target, process or inhibit somatostatin receptors, such as octreotide and SOM230. Tumor cell injury methods refer to methods such as ionizing radiation. The term "ionizing radiation" mentioned above and below means ionizing radiation that occurs as electromagnetic rays (such as X-rays and gamma rays) or particles (such as alpha and beta particles). Ionizing radiation Shooting is provided in (but not limited to) radiation therapy and is known in the art. See Hellman, Principles of Radiation Therapy, Cancer, in Principles and Practice of Oncology, eds., Devita et al., 4th edition, volume 1, pages 248 to 275 (1993).

Also includes EDG binders and ribonucleotide reductase inhibitors. The term "EDG binding agent" as used herein refers to a type of immunosuppressant that regulates lymphocyte recirculation, such as FTY720. The term "ribonucleotide reductase inhibitor" refers to pyrimidine or purine analogs, including (but not limited to) fludarabine and/or cytosine arabinoside (ara-C), 6-thioguanine, 5-Fluorouracil, cladribine, 6-mercaptopurine (especially in combination with ara-C for anti-ALL) and/or pentostatin. Ribonucleotide reductase inhibitors are particularly hydroxyurea or 2-hydroxy-1H-isoindole-1,3-dione derivatives.

Also includes (specifically) VEGF compounds, proteins or monoclonal antibodies, such as 1-(4-chloroanilinyl)-4-(4-pyridylmethyl)phthalazine or its pharmaceutically acceptable salts , Succinic acid 1-(4-Chloroanilino)-4-(4-pyridylmethyl)phthalazine; Angiostatin ^TM ; Endostatin ^TM ; anthranilic acid amide; ZD4190; ZD6474; SU5416; SU6668; Bevar Monoclonal antibody (bevacizumab); or anti-VEGF antibody or anti-VEGF receptor antibody (such as rhuMAb and RHUFab), VEGF aptamer (such as pigatanib (Macugon)); FLT-4 inhibitor, FLT-3 inhibitor , VEGFR-2 IgGI antibody, Angiozyme (RPI 4610) and Bevacizumab (Avastin ^TM ).

Photodynamic therapy as used herein refers to the use of certain chemicals known as light-sensitive compounds to treat or prevent cancer. Examples of photodynamic therapy include treatment with ^{compounds such as Visudyne™} and porphenim sodium.

Angiogenesis-inhibiting steroids as used herein refer to compounds that block or inhibit angiogenesis, such as, for example, anecortave, triamcinolone, hydrocortisone, 11-α-epihydrocortisone Pine (11-α-epihydrocotisol), cortexolone (cortexolone), 17α-hydroxyprogesterone, corticosterone, deoxycorticosterone, testosterone, estrogen And dexamethasone.

Corticosteroid-containing implants refer to compounds such as fluocinolone and dexamethasone.

Other chemotherapeutic compounds include (but are not limited to) plant alkaloids, hormone compounds and antagonists; biological response modifiers, preferably lymphokines or interferons; antisense oligonucleotides or oligonucleotide derivatives; shRNA Or siRNA; or miscellaneous compounds or compounds with other or unknown mechanisms of action.

The compounds of the present invention can also be used as co-therapeutic compounds used in combination with other bulk drugs (such as anti-inflammatory, bronchodilator or antihistamine bulk drugs), especially for the treatment of obstructive or inflammatory airway diseases (such as those mentioned above) Or), for example as an enhancer of the therapeutic activity of these drugs or as a way to reduce the required dose or potential side effects of these drugs. The compound of the present invention can be mixed with other drug substances in a fixed pharmaceutical composition, or it can be administered separately before, during or after the other drug substances. Therefore, the present invention includes a combination of the compound of the present invention as described above and an anti-inflammatory, bronchodilator, antihistamine or antitussive bulk drug, the compound of the present invention and the bulk drug are in the same or different pharmaceutical compositions.

Suitable anti-inflammatory drugs include steroids, specifically glucocorticoids, such as budesonide, beclomethasone dipropionate, fluticasone propionate, ciclesonide or mometasone furoate; non-steroidal glucocorticoids Hormone receptor agonists; LTB4 antagonists, such as LY293111, CGS025019C, CP-195543, SC-53228, BIIL 284, ONO 4057, SB 209247; LTD4 antagonists, such as montelukast and zalukast (zafirlukast); PDE4 inhibitors, such as cilomilast (Ariflo® GlaxoSmithKline), Roflumilast (Byk Gulden), V-11294A (Napp), BAY19-8004 (Bayer), SCH- 351591 (Schering-Plough), Arofylline (Almirall Prodesfarma), PD189659/PD168787 (Parke-Davis), AWD-12-281 (Asta Medica), CDC-801 (Celgene), SeICID (TM) CC -10004(Celgene), VM554/UM565 (Vernalis), T-440 (Tanabe), KW-4490 (Kyowa Hakko Kogyo); A2a agonists; A2b antagonists; and β-2 adrenergic receptor agonists, such as albuterol/salbutamol ), oxinaline, terbutaline, salmeterol, fenoterol, procaterol, and especially formoterol and its pharmaceutically acceptable salts. Suitable bronchodilator drugs include anticholinergic or antimuscarinic compounds, specifically ipratropium bromide, oxitropium bromide, tiotropium bromide and CHF 4226 (Chiesi), and pyrrolose ( glycopyrrolate).

Suitable antihistamine raw materials include cetirizine hydrochloride (cetirizine), acetaminophen, chlorbenzazole fumarate, promethazine, loratidine, desloratidine, and diphenhydramine ) And fexofenadine hydrochloride, activastine, astemizole, azelastine, ebastine, epinastine ), mizolastine and tefenadine.

Other available combinations of the compounds of the present invention and anti-inflammatory drugs are those combining them with the following: chemokine receptors (e.g. CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8, CCR-9 and CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5) antagonists, especially CCR-5 antagonists, such as Schering-Plough antagonists SC-351125, SCH-55700 and SCH-D, and Takeda antagonists, such as N-[[4-[[[6,7-dihydro-2-(4-methylphenyl)-5H-benzo-cyclohepten-8-yl] Carbonyl]amino]phenyl]-methyl]tetrahydro-N,N-dimethyl-2H-piperan-4-ammonium chloride (TAK-770).

The structure of the active compound identified by the code, common name or brand name can be obtained from the current edition of the standard compendium "The Merck Index" or a database (for example, Patents International (for example, IMS World Publications)).

The compounds of the present invention can also be used in combination with known treatment methods, such as administration of hormones or radiation. In some embodiments, the provided compounds are used as radiosensitizers, particularly for the treatment of tumors that are not sensitive to radiotherapy.

The compound of the present invention can be administered alone or in combination with one or more other therapeutic compounds, and possible combination therapy can be in the form of fixed combination or staggered or independent administration of the compound of the present invention and one or more other therapeutic compounds, or combined administration With a fixed combination and one or more other therapeutic compounds. In addition, the compounds of the present invention can be specifically administered for tumor therapy in combination with chemotherapy, radiation therapy, immunotherapy, phototherapy, surgical intervention, or a combination thereof. Long-term therapy is also feasible, as is adjuvant therapy in the context of other treatment strategies as described above. Other possible treatments are therapies that maintain the patient's condition after tumor regression, or even chemopreventive therapy, for example in at-risk patients.

These other agents can be administered separately from the composition containing the compound of the invention as part of a multiple dosing regimen. Alternatively, these agents may be part of a single dosage form, mixed with the compound of the invention in a single composition. If administered as part of a multiple dosing schedule, the two active agents can be provided simultaneously, sequentially, or within a period of time (usually within five hours of each other).

As used herein, the term "combination" and related terms refer to the simultaneous or sequential administration of the therapeutic agents of the invention. For example, the compound of the present invention and another therapeutic agent can be administered simultaneously or sequentially in separate unit dosage forms, or together in a single unit dosage form. Therefore, the present invention provides a single unit dosage form containing a compound of the present invention, another chemotherapeutic agent, and a pharmaceutically acceptable carrier, adjuvant or vehicle.

The amount of both the compound of the invention that can be combined with carrier materials to produce a single dosage form and another therapeutic agent (in those compositions containing another therapeutic agent as described above) will depend on the subject being treated and the specific mode of administration And change. Preferably, the composition of the present invention should be formulated so that a dose of 0.01 to 100 mg/kg body weight/day of the compound of the present invention can be administered.

In their compositions containing another therapeutic agent, the other therapeutic agent and the compound of the present invention may act synergistically. Therefore, the amount of another therapeutic agent in these compositions will be less than the amount required in a monotherapy using only the therapeutic agent. In these compositions, another therapeutic agent can be administered at a dose of 0.01 to 1,000 μg/kg body weight/day.

The amount of another therapeutic agent present in the composition of the present invention will not exceed the amount normally administered in a composition containing the therapeutic agent as the sole active agent. Preferably, the amount of another therapeutic agent in the currently disclosed composition will be in the range of about 50% to 100% of the amount normally present in a composition containing the agent as the only therapeutically active agent.

The compounds of the present invention or their pharmaceutical compositions can also be incorporated into compositions for coating implantable medical devices (such as prostheses, artificial valves, vascular grafts, stents, and catheters). For example, vascular stents have been used to overcome restenosis (restenosis of blood vessel walls after injury). However, patients using stents or other implantable devices are at risk of forming blood clots or activating platelets. These undesired effects can be prevented or alleviated by pre-coating the device with a pharmaceutically acceptable composition containing a kinase inhibitor. The implantable device coated with the compound of the present invention is another embodiment of the present invention.

Instance

As described in the examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures. It should be understood that although the general method describes the synthesis of certain compounds of the present invention, the following general methods and other methods known to those of ordinary skill can be applied to all the compounds described herein and the subclasses and types of each of these compounds .

Example 1. Synthesis of 2-(2,6-difluorophenyl)-4-(indoline-6-ylamino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine -5-one, I-1

Synthesis of compound 1.2. At room temperature, to a solution of compound 1.1 (300mg, 0.69mmol, 1.0 equivalent) in 1-butanol (9.0mL) was added 6-aminoindoline-1-carboxylic acid tert-butyl ester (162mg, 0.69mmol) , 1.0 equivalent) and DIPEA (224 mg, 1.74 mmol, 2.5 equivalent). The reaction mixture was heated at 85 to 90°C for 2 hours. After completing the reaction, the mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine solution, dried over sodium sulfate, and concentrated under reduced pressure. The crude material was purified by column chromatography to provide compound 1.1 (302 mg, 69.04%), MS (ES): m/z 630.6 [M+H] ⁺ .

Synthesis of compound I-1. A solution of compound 1.1 (302 mg, 0.48 mmol, 1.0 equivalent) in HBr/HOAc solution (33%, 6.0 mL) was stirred at room temperature for 45 minutes. After completing the reaction, the reaction mixture was poured into cold water, neutralized with NaHCO ₃ and extracted with ethyl acetate (75 ml x 2). The solvent was removed under reduced pressure, and the crude material was purified by column chromatography to obtain pure compound I-1 (105 mg, 57.7%). MS(ES): m/z -380.3[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ ): δ 8.88 (s, 1H), 8.85 (s, 1H), 7.61-7.57 (m, 1H), 7.28-7.24(t, 2H), 6.97-6.93(m, 2H), 6.81-6.79(dd, 1H), 5.62(s, 1H), 4.45(s, 2H), 3.42-3.40(t, 2H), 2.87-2.83(t, 2H).

Example 2. Synthesis of 2-(2,6-difluorophenyl)-4-((3,3-dimethylindolin-6-yl)amino)-6,7-dihydro-5H-pyrrole And [3,4-d]pyrimidin-5-one, I-2

Synthesis of compound 2.1. At room temperature, to a solution of compound 1.1 (130 mg, 0.3 mmol, 1.0 equivalent) in 1-butanol (5.0 mL) was added 6-amino-3,3-dimethylindoline-1-carboxylic acid Tributyl ester (79 mg, 0.3 mmol, 1.0 equivalent) and diisopropylethylamine (97 mg, 0.75 mmol, 2.5 equivalent). The reaction was heated at 85 to 90°C for 2 hours. After completing the reaction, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine solution, dried over sodium sulfate, and concentrated under reduced pressure. The crude material was purified by column chromatography to obtain pure compound 2.1 (110 mg, 65.53%), MS (ES): m/z 558.6 [M+H] ⁺ .

Synthesis of compound I-2. A solution of compound 2.1 (110 mg, 0.19 mmol, 1.0 equivalent) in hydrogen bromide/CH ₃ COOH (33%, 4 ml) was stirred at room temperature for 45 minutes. After completing the reaction, the mixture was poured into water and neutralized _{with NaHCO 3.} The product was extracted with ethyl acetate (75 mL x 2). At 45°C, the solvent was removed under reduced pressure. The crude material was purified by column chromatography and preparative TLC to obtain pure compound I-2 (20 mg, 24.9%). MS(ES): m/z -408.4[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ ): δ 8.88(s, 1H), 8.85(s, 1H), 7.62-7.57(m, 1H), 7.28-7.24(t, 2H), 6.94-6.92(m, 2H), 5.60(s, 1H), 4.45(s, 2H), 3.167-3.163(d, 2H), 1.23(s, 6H) .

Example 3. Synthesis of compound 2-(2,6-difluorophenyl)-4-((2,2-dimethylindolin-6-yl)amino)-6,7-dihydro-5H- Pyrrolo[3,4-d]pyrimidin-5-one, I-3

Synthesis of compound 3.2. At room temperature, under an argon atmosphere, to a solution of compound 3.1 (1 g, 4.60 mmol, 1.0 equivalent) in cyclohexane (8 mL) was added 2,2,2-trichloroacetimide tert-butyl ester (2.05 ml, 11.51 mmol, 2.5 equivalents), BF ₃ -Et ₂ O (0.11 ml), for 15 minutes. The reaction mixture was stirred at room temperature for 16 hours. After completing the reaction, the mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated NaHCO _{3 , dried over Na 2} SO ₄ and concentrated under reduced pressure. The crude material was purified by column chromatography to provide compound 3.2 (0.27 g, 21.3%). MS(ES): No ionization [M+H] ⁺ .

Synthesis of compound 3.3. Compound 3.2 (0.2 g, 0.73 mmol) was dissolved in methyl chloroformate (2 mL). The reaction mixture was heated at 80°C for 16 hours. After completing the reaction, water was added to the mixture, and extracted with dichloromethane. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude reaction mixture was purified by column chromatography to obtain compound 3.3 (0.12 g, 49.49%). MS(ES): m/z has no ionization effect [M+H] ⁺ .

Synthesis of compound 3.4. To a solution of compound 3.3 (0.050g, 0.150mmol, 1.0 equivalent) in xylene was added cesium carbonate (0.068g, 0.211mmol), tricyclohexylphosphine tetrafluoroborate (0.004g, 0.009mmol, 0.06 equivalent), and Tetrapentane Acid (0.005g, 0.0452mmol, 0.3 equivalent) and palladium acetate (0.001g, 0.0045mmol, 0.03 equivalent). The reaction mixture was degassed for 10 minutes using an argon atmosphere. The reaction was stirred at 140°C for 1 hour. After completing the reaction, the mixture was poured into water, and the product was extracted with ethyl acetate (50 mL x 2). The solvent was removed at 45°C under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain pure compound 3.4 (0.035g, 92.63%). MS (ES): m/z 251 [M+H] ⁺ .

Synthesis of compound 3.5. Under a nitrogen atmosphere, to a suspension of Pd/C (10 mg) in methanol (10 ml) was added compound 3.4 (0.085 g, 0.339 mmol, 1.0 equivalent). The mixture was purged _{with H 2} (gas) at room temperature for 2 hours. After completing the reaction, the mixture was filtered through Celite. The solvent was removed at 45° C. under reduced pressure to obtain compound 3.5 (0.070 g, 93.6%). MS (ES): m/z 221.3 [M+H] ⁺ .

Synthesis of compound 3.6. At room temperature, to a solution of compound 3.5 (130mg, 0.301mmol, 1.0 equivalent) in 1-butanol (2.0mL) was added compound 3.5 (72mg, 0.331mmol, 1.1 equivalent) and DIPEA (0.15ml, 0.903mmol, 3 equivalents). The reaction was heated at 90°C for 3 hours. After completing the reaction, the mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saline solution. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by column chromatography to obtain pure compound 3.6 (120 mg, 64.75%), MS (ES): m/z 616.7 [M+H] ⁺ .

Synthesis of compound I-3. A solution of compound 3.6 (0.120 g, 0.194 mmol, 1.0 equivalent) in HBr/HOAc solution (33%, 3 mL) was stirred at room temperature for 45 minutes. After the reaction was completed, the mixture was poured into cold water, neutralized with NaHCO ₃ , and the product was extracted with ethyl acetate (75 ml x 2). The solvent was removed at 45° C. under reduced pressure to obtain a crude material, which was purified to obtain pure compound I-3 (10 mg, 12.59%). MS(ES): m/z -408.3[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ ): δ 8.87 (d, 2H), 7.59 (m, 1H), 7.25 (dd, 2H) , 6.91 (d, 2H), 6.75 (dd, 1H), 5.64 (s, 1H), 4.45 (s, 2H), 2.67 (s, 2H), 1.20 (d, 6H).

Example 4. Synthesis of 4-((5-((1R,5S)-8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyridin-2-yl)amino)-2- (2,6-Difluorophenyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, I-4

Synthesis of compound 4.2. To 4.1 (0.2g, 0.9852mmol, 1.0 equivalent) in DMSO (3ml) was added TBAI (0.036g, 0.0985mmol, 0.1 equivalent), (1R,5S)-8-oxa-3-azabicyclo[ 3.2.1] Octane (0.162 g, 1.083 mmol, 1.1 equivalents) and K ₂ CO ₃ (0.544 g, 3.94 mmol, 4 equivalents). The reaction mixture was heated at 120°C for 2 hours. The reaction mixture was poured into water, and the product was extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain 4.2 (0.120 g, 51.77%). MS (ES): m/z 236 [M+H] ⁺ .

Synthesis of compound 4.3. Under a nitrogen atmosphere, to a solution of compound 4.2 (0.120 g, 0.5106 mmol, 1.0 equivalent) in methanol (5 mL) was added 10% Pd/C (0.012 mg). The suspension was purged with H ₂ gas for 3 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain crude compound 4.3 (0.105g), which was used as it is in the next step, MS(ES): m/z 206.0[M+H] ⁺ .

Synthesis of compound 4.5. To a solution of compound 4.4 (0.2g, 0.4645mol, 1.0 equivalent) in 1,4-dioxane (3mL) was added compound 4.3 (0.104g, 0.5109mmol, 1.1 equivalent) and potassium carbonate (0.160g, 1.161mmol, 2.5 equivalents). The reaction mixture was degassed with argon for 10 minutes, and then Pd ₂ (dba) ₃ (0.042 g, 0.0464 mmol, 0.1 equivalent) and Xantphos (0.053 g, 0.0929 mmol, 0.2 equivalent) were added. Degas the suspension for an additional 5 minutes. The reaction was then heated at 110°C for 2 hours. After completing the reaction, the reaction mixture was poured into water, and the product was extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain pure 4.5 (0.12 g, 43.1%). MS (ES): m/z 600.3 [M+H] ⁺ .

Synthesis of compound I-4. Compound 4.5 was dissolved in HBr/acetic acid (2ml) and stirred at room temperature for 1 hour. After completing the reaction, the mixture was poured into water and basified with saturated bicarbonate solution, and the product was extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain pure compound 1-4 (0.052 g, 57.8%). MS(ES): m/z 450.21[M+H] ⁺ ; ¹ H NMR (DMSO-d ₆ , 400MHZ): 9.47(s, 1H), 8.80(s, 1H), 8.34(s, 1H), 7.94 (d, 1H), 7.60(m, 1H), 7.40(dd, 1H), 7.25(m, 2H), 7.10(d, 1H), 4.40(s, 4H), 3.36(t, 2H), 2.80( dd, 2H), 1.83 (s, 4H).

Example 5. Synthesis of 4-((4-(8-oxa-3-azabicyclo[3.2.1]octane-3-carbonyl)phenyl)-amine Yl)-2-(2,6-difluorophenyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-5-one, I-5

At 0°C, to a solution of 5.1 (0.1g, 0.26mmol, 1.0 equivalent) in anhydrous THF (5.0mL) was added EDCl-HCl (0.1g, 0.52mmol, 2.0 equivalent) and HOBt (0.069g, 0.39mmol) , 1.5 equivalents). The solution was stirred at 0°C for 1 hour. 8-oxa-3-azabicyclo[3.2.1]octane (0.035g, 0.312mmol, 1.2 equivalents) and DIPEA (0.1g, 0.78mmol, 3.0 equivalents) were added successively. The reaction mixture was allowed to warm to room temperature and stirred overnight. After completing the reaction, the mixture was poured into water and extracted with ethyl acetate (50 mL x 2). The organic layer was washed with brine solution, dried over sodium sulfate, and concentrated under reduced pressure. The crude material was purified by column chromatography to obtain pure compound I-5 (65 mg, 52.1%). MS(ES): M/z 478.53[M+H] ⁺ , ¹ H NMR (400MHz, DMSO-d ₆ ): δ 9.226 (s, 1H), 8.963 (s, 1H), 7.828-7.849 (d, 2H) ), 7.568-7.641 (m, 1H), 7.373-7.394 (d, 2H), 7.249-7.343 (m, 2H), 4.505 (2H), 4.358 (m, 2H), 7.193 (m, 1H), 3.727- 3.763 (m, 1H), 2.950-2.976 (m, 2H), 1.771 (m, 6H).

Example 6. Synthesis of 2-(4-((2-(2,6-difluorophenyl)-5-oxo-6,7-dihydro-5H-pyrrolo-[3,4-d]pyrimidine -4-yl)amino)phenyl)-2-hydroxypropionic acid, I-6

Synthesis of compound 6.2. At 0℃, add 6.1 (0.76g, 6.15mmol, 0.5 equivalent) and ethyl 2-chloropropionate to a suspension of NaH (0.740g, 18.45mmol, 1.5eq) in DMF (10mL) via a syringe. Esters (1.68 g, 12.3 mmol, 1 equivalent). The reaction was stirred at 0°C for 1 hour and then at room temperature for 2 hours. Benzaldehyde (0.98 g, 9.22 mmol, 0.75 equivalent) was added, and the reaction was purged with oxygen for 16 hours. The reaction mixture was quenched with ice; then dilute HCl was added. The product was extracted with ethyl acetate (20 mL x 2). The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure. The crude material was purified using column chromatography to provide 6.2 (0.466 g, 31.6%). MS(ES): m/z has no ionization effect [M+H] ⁺ .

Synthesis of compound 6.3. To a solution of 6.2 (0.266g, 1.112mmol, 1.0 equivalent) in methanol (3mL) and water (3mL) was added NH ₄ Cl (0.350g, 5.564mmol, 5.0 equivalent) and iron powder (0.311g, 5.564mmol, 5.0 equivalents) for 1 hour. The reaction mixture was heated at 80°C for 2 hours. The reaction mixture was filtered through Celite, washed with methanol, and the resulting filtrate was concentrated under reduced pressure to obtain the crude substance 6.3 (0.2g, 85.96%), which was used in the next step as it is, MS(ES): m/z 210[M+H] ⁺ .

Synthesis of compound 6.4. To a solution of 1.1 (0.3 g, 0.69 mmol, 1.0 equivalent) in 1-butanol (5 mL) was added 6.3 (0.159 g, 0.764 mmol, 1.1 equivalent) and DIPEA (0.4 ml, 2.08 mmol, 3 equivalent). The reaction was stirred at 100°C for 2 hours. After completing the reaction, the reaction mixture was poured into water, and the product was extracted with EtOAc (100 mL x 2). The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure. The crude material was purified by column chromatography to provide 6.4 (0.3g, 71.4%). MS (ES): m/z 605.3 [M+H] ⁺ .

Synthesis of compound 6.5. Compound 6.4 (0.3 g, 0.496 mmol, 1.0 equivalent) was dissolved in HBr/HOAc mixture (3 mL) and stirred at room temperature for 1 hour. After completion, the reaction mixture was poured into water and basified with saturated bicarbonate solution. The product was extracted with EtOAc (100 mL x 2). The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure. The crude material was purified using column chromatography to provide 6.5 (0.125 g, 55.44%). MS (ES): m/z 455.2 [M+H] ⁺ .

Synthesis of compound I-6. To a solution of 6.5 (0.125 g, 0.275 mmol, 1.0 equivalent) in MeOH (3 mL) and water (3 mL) was added NaOH (0.066 g, 1.65 mmol, 6.0 equivalent). The reaction was stirred at room temperature for 1 hour. The solvent was concentrated under reduced pressure, and the reaction mixture was acidified with dilute HCl and extracted with EtOAc (25 mL x 2). The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure. The crude material was triturated with ether and pentane to obtain pure compound I-6 (0.08 g, 68.2%). MS (ES): m/z 427.3 [M+H] ⁺ . ¹ H NMR(DMSO-d ₆ ,400MHz): 12.67(s,1H),9.081(s,1H),8.90(s,1H),7.70(d,2H),7.60(m,1H),7.47(d , 2H), 7.27 (t, 2H), 5.76 (s, 1H), 4.48 (s, 2H), 1.6 (s, 3H).

Example 7. Synthesis of (S)-2-(4-((2-(2,6-difluorophenyl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4- d]Pyrimidine-4-yl)amino)phenyl)-2-hydroxypropionic acid, I-7

The compound I-6 was separated to obtain the compound I-7 . MS(ES): m/z [M+H] ⁺ , ¹ H NMR (400MHz, DMSO-d ₆ ): δ 12.65 (s, 1H), 9.079 (s, 1H), 8.904 (s, 1H), 7.70 -7.72 (d, 2H), 7.60 (m, 1H), 7.58 (d, 2H), 7.25-7.30 (m, 2H), 4.48 (s, 2H), 1.60 (s, 3H).

Example 8. Synthesis of (R)-2-(4-((2-(2,6-difluorophenyl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4- d]Pyrimidine-4-yl)amino)phenyl)-2-hydroxypropionic acid, I-8

Compound I-6 for chiral separation to give Compound I-8. MS(ES): m/z [M+H] ⁺ , ¹ H NMR (400MHz, DMSO-d ₆ ): δ 9.06 (s, 1H), 8.88 (s, 1H), 7.68-7.70 (d, 2H) , 7.58-7.62 (m, 1H), 7.47-7.49 (d, 2H), 7.25-7.29 (m, 2H), 4.47 (s, 2H), 1.58-1.62 (d, 3H).

Example 9. Synthesis of the compound 2-amino-2-(4-((2-(2,6-difluorophenyl)-5-oxo-6,7-dihydro-5H-pyrrolo[3, 4-d]pyrimidin-4-yl)amino)phenyl)-N-ethylpropionamide, I-9

Synthesis of compound 9.2. To a solution of 9.1 (1 g, 7.1 mmol, 1.0 equivalent) in CH ₂ Cl ₂ (10 mL) was added benzophenone imine (1.3 g, 7.1 mmol, 1.0 equivalent). The reaction was stirred at ambient temperature for 16 hours. After completing the reaction, the mixture was poured into water (200 mL) and extracted with EtOAc (100 mL x 3). The organic layer was washed with a saturated saline solution, dried over sodium sulfate, and concentrated under reduced pressure. The crude material was purified by column chromatography to obtain 9.2 (1.4 g, 54%). MS (ES): m/z 268.33 [M+H] ⁺ .

Synthesis of compound 9.3. At -78℃ , add 9.2 (1.4g, 0.52mmol, 1.0 equivalent) and 1-bromo-3-nitrobenzene (2.1g, 10.5mmol, 2.0 equivalent) in THF (18mL) and DMF (4mL) After stirring the solution, a solution of potassium tertiary butoxide (0.88 g, 10.5 mmol, 2.0 equivalents) in THF (5 mL) was added dropwise. The reaction mixture was stirred for an additional 30 minutes and then treated with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (1.4 g, 6.3 mmol, 1.20 equivalents) in THF (2 mL). After stirring for 5 minutes, the cooling bath was removed and the reaction mixture was allowed to reach ambient temperature. The compound was directly purified by column chromatography to obtain pure 9.3 (1.2 g, 49.03%), MS (ES): m/z 468.3 [M+H] ⁺ .

Synthesis of compound 9.4. To the solution of 9.3 (1.2 g) in acetonitrile was added 6N HCl solution (20 mL). The reaction was stirred at room temperature for 6 hours. After completion, the reaction mixture was poured into saturated Na ₂ CO ₃ (500 mL) and extracted with EtOAc (200 mL×3). The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain pure 9.4 (0.7 g, 90%). MS (ES): m/z 304.11 [M+H] ⁺ .

Synthesis of compound 9.5. To a solution of 9.4 (500 mg, 1.65 mmol, 1.0 equivalent) in EtOAc:H ₂ O (10 mL) was added Boc anhydride (680 mg, 3.1 mmol, 1.9 equivalents) and lithium carbonate (260 mg, 3.6 mmol, 2.2 equivalents). The reaction was heated at 60°C for 24 hours. After completion, the reaction mixture was poured into water (100 mL) and extracted with EtOAc (50 mL x 3). The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain 9.5 (0.55 g, 59.1%). MS (ES): m/z 404.11 [M+H] ⁺ .

Synthesis of compound 9.6. To a solution of 9.5 (500 mg, 1.24 mmol, 1.0 equivalent) in MeOH/H ₂ O water (10 mL) was added LiOH (0.16 g, 3.7 mmol, 3 equivalents) and stirred at ambient temperature for 3 hours. After completion, the reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (50 mL×3). The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to obtain 9.6 (0.5 g, 94%). MS (ES): m/z 390.2 [M+H] ⁺ .

Synthesis of compound 9.7. At 0°C, to a solution of 106.6 (500mg, 1.28mmol, 1.0 equivalent) in THF (2.0mL) was added ethylamine (1M solution in THF) (0.7ml, 1.59mmol, 1.2 equivalent), HATU (720mg, 1.92mmol, 1.5 equivalents) and DIPEA (0.7ml, 3.8mmol, 3 equivalents). The reaction was stirred at room temperature for 16 hours. After completion, the reaction mixture was poured into water (100 mL) and extracted with EtOAc (50 mL x 3). The organic layers were combined, washed with saturated saline solution, dried over sodium sulfate, and concentrated under reduced pressure. The crude material obtained was purified by column chromatography to obtain 9.7 (0.3 g, 56%). MS (ES): m/z 417.27 [M+H] ⁺ .

Synthesis of compound 9.8. Under a nitrogen atmosphere, to a suspension of Pd/C (100 mg) in MeOH (15 ml) was added 9.7 (0.3 g, 0.75 mmol, 1.0 equivalent). 12 hours reaction mixture was purged with H ₂ gas at room temperature. After completing the reaction, the reaction mixture was filtered through Celite. The solvent was removed under reduced pressure to obtain compound 9.8 (0.12 g, 54%). MS (ES): m/z 308.7 [M+H] ⁺ .

Synthesis of compound 9.9. At room temperature, to a solution of 1.1 (91mg, 0.21mmol, 1.0 equivalent) in 1-butanol (2.0mL) was added 1.7 (65mg, 0.21mmol, 1.0 equivalent) and DIPEA (0.11ml, 0.63mmol, 3 equivalents) ). The reaction was stirred at 90°C for 3 hours. After completion, the mixture was poured into water (50 mL) and extracted with EtOAc (30 mL x 3). The organic layers were combined, washed with saturated saline solution, dried over sodium sulfate, and concentrated under reduced pressure. The crude material was purified by column chromatography to obtain 9.9 (0.08 g, 54%). MS (ES): m/z 703.2 [M+H] ⁺ .

Synthesis of compound I-9. A solution of 9.9 (0.08 g, 0.13 mmol, 1.0 equivalent) in HBr/HOAc solution (33%, 3 mL) was stirred at room temperature for 45 minutes. After completing the reaction, the mixture was poured into cold water, neutralized with NaHCO ₃ and extracted with EtOAc (75 mL x 2). The solvent was removed under reduced pressure, and the crude material was purified by column chromatography to obtain I-9 (35 mg, 68%). MS(ES): m/z -408.3[M+H] ⁺ , ¹ H NMR (400MHz, DMSO-d ₆ ): δ 9.04(s,1H),8.89(s,1H),7.90(t,1H) ,7.68(d,2H),7.60(t,1H),7.43(d,2H),7.27(t,2H),4.47(s,2H),3.07-3.02(m,2H),1.51(d,3H) ),0.98(t,3H).

Example 10. Synthesis of 2-(2,6-difluorophenyl)-4-((3,3-dimethyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-6 -Amino)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, I-10

Synthesis of compound 10.2. To a solution of 10.1 (7.0g, 54.54mmol, 1.0 equivalent) and pivaloyl chloride (6.7ml, 57.0mmol, 1.05 equivalent) in toluene was added Et ₃ N (7.7ml, 57.0mmol, 2.5 equivalent), and heated at 60 Stir at ℃ for 16 hours. After completion, the reaction mixture was poured into water (500 mL) and extracted with EtOAc (200 mL x 3). The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain pure 10.2 (9.0 g, 77.7%). MS (ES): m/z 213.3 [M+H] ⁺ .

Synthesis of compound 10.3. At -78°C, to a solution of 10.2 (9 g, 42 mmol, 1 equivalent) in THF (90 mL) was added tertiary butyl lithium (1.6 M in pentane) (62 ml, 90.0 mmol, 2.2 equivalents). The reaction mixture was stirred at -78°C for 3 hours. A solution of iodine (12.7 g, 50.0 mmol, 1.2 equivalents) in THF (40 mL) was added dropwise at -78°C. The reaction was warmed to ambient temperature and stirred for 2 hours. After completion, the reaction mixture was poured into dilute HCl (200 mL) and extracted with ethyl acetate (200 mL×3). The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain 10.3 (8.0g, 55.84%), MS (ES): m/z 339.3 [M +H] ⁺ .

Synthesis of compound 10.4. To a solution of 10.3 (8.0 g, 23.63 mmol, 1.0 equivalent) in 1,4 dioxane was added a 2N HCl solution (20 mL). The reaction was stirred at 80°C for 3 hours. The reaction mixture was poured into saturated NaHCO ₃ solution (500 mL) and extracted with EtOAc (200 mL x 3). The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to obtain a crude product

It was purified by column chromatography to obtain 10.4 (4.2g, 70%). MS (ES): m/z 255.46 [M+H] ⁺ .

Synthesis of compound 10.5. To a solution of 10.4 (1.5g, 5.9mmol, 1.0 equivalent) in THF was added 3-bromo-2-methylprop-1-ene (0.95g, 7.08mmol, 1.2 equivalent) and potassium tertiary butoxide (0.8g , 7.08 mmol, 1.2 equivalents). The reaction was stirred at room temperature for 3 hours. The reaction mixture was poured into water (200 mL) and extracted with EtOAc (100 mL X 3). The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain 110.5 (1.5 g, 82%). MS (ES): m/z 309.55 [M+H] ⁺ .

Synthesis of compound 10.6. At room temperature under argon advocacy, (1.5g, 4.48mmol, 1.0 eq) in toluene containing 10.5 to (15mL) was added a solution of potassium formate (500mg, 5.8mmol, 1.2 eq.), Tetrabutylammonium chloride (1.6 g, 5.8 mmol, 1.2 equivalents) and Et ₃ N (2 mL, 1.4 mmol, 3 equivalents) for 15 minutes. _{Under argon blowing, Pd(OAc) 2} (53 mg, 0.29 mmol, 0.1 equivalent) was added to the above reaction mixture for 10 minutes. The reaction mixture was heated at 100°C for 1 hour. After completing the reaction, the reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (50 mL×3). The organic layers were washed with brine solution, combined and dried over sodium sulfate, and concentrated under reduced pressure. The crude material obtained was purified by column chromatography to obtain 10.6 (0.8 g, 90%). MS (ES): m/z 183.5 [M+H] ⁺ .

Synthesis of compound 10.7. To a solution of 10.6 (0.6 g, 3.2 mmol, 1.0 equivalent) and Boc-anhydride (1.0 g, 4.86 mmol, 1.5 equivalent) in dichloromethane was added DMAP (39 mg, 0.32 mmol, 0.1 equivalent). The reaction was stirred at room temperature for 1 hour. After completion, the mixture was poured into water (100 mL) and extracted with EtOAc (50 mL x 3). The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to obtain a crude material. The crude material was purified by column chromatography to provide 10.7 (0.8g, 86%). MS (ES): m/z 283.2 [M+H] ⁺ .

Synthesis of compound 10.8. Under argon blowing at room temperature, to a solution of 10.7 (0.2g, 0.70mmol, 1.0 equivalent) in anhydrous THF (5.0mL) was added LHMDS (1.0M in THF) (2.1ml, 2.1mmol, 3.0 equivalent) , Lasts 15 minutes. _{Under argon blowing, Pd 2} (dba) ₃ (62 mg, 0.068 mmol, 0.1 equivalent) and 2-biphenyl) di-tertiary butyl phosphine (48 mg, 0.021 mmol, 0.2 equivalent) were added to the above reaction mixture for 10 minute. The reaction mixture was heated at a temperature of 60°C for 2 hours. After completing the reaction, the reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (30 mL×3). The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain crude material. The crude material was purified by column chromatography to provide 10.8 (0.08g, 43.0%). MS (ES): m/z 264.2 [M+H] ⁺ .

Synthesis of compound 10.9. Under argon blowing at room temperature, to a solution of 4.4 (0.10g, 0.23mmol, 1.0 equivalent) in anhydrous dioxane (5.0mL) was added 10.8 (67mg, 0.23mmol, 1.0 equivalent), K ₂ CO ₃ ( 0.095 g, 0.60 mmol, 3.0 equivalents) for 15 minutes. _{Under argon blowing, Pd 2} (dba) ₃ (21 mg, 0.023 mmol, 0.1 equivalent) and Xantphos (26 mg, 0.046 mmol, 0.2 equivalent) were added to the above reaction mixture for 10 minutes. The reaction mixture was heated at a temperature of 105°C for 3 to 4 hours. After completing the reaction, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layers were combined, washed with brine, then dried over sodium sulfate, and concentrated under reduced pressure to obtain a crude material. The crude material was purified by column chromatography to provide 10.9 (0.08g, 53.0%). MS (ES): m/z 658.20 [M+H] ⁺ .

Synthesis of compound I-10. A solution of 10.9 (80 mg) in HBr/HOAc solution (33%, 5 ml) was stirred at room temperature for 1 hour. After completing the reaction, the reaction mixture was poured into cold water, neutralized with NaHCO ₃ and extracted with ethyl acetate (50 ml X 2). The solvent was removed under reduced pressure, and the resulting crude material was purified by column chromatography to obtain compound I-10 (30 mg, 60.0%). MS(ES): m/z 501.58[M+H] ⁺ , ¹ H NMR (400MHz, DMSO-d ₆ ): δ 9.48(s,1H), 8.82(s,1H), 8.38(s,1H), 7.60-7.52 (m, 1H), 7.27-7.23 (m, 3H), 6.54 (s, 1H), 6.15 (d, 1H), 4.41 (s, 2H), 3.20 (s, 2H), 1.21 (s, 6H).

Example 12. Synthesis of 2-(2,6-difluorophenyl)-4-((4-((1,3-dihydroxyprop-2-yl)oxy)phenyl)amino)-6,7 -Dihydro-5H-pyrrolo[3,4-d]pyrimidin-5-one, I-12

Synthesis of compound 12.1. At room temperature, to a solution of 1.1 (0.140g, 0.324mmol, 1.0 equivalent) in DMSO (2mL) was added 4-(oxabutan-3-yloxy)aniline (0.051g, 0.308mmol, 0.95 equivalent) ) And DIPEA (0.16ml, 0.974mmol, 3.0 equivalents). The reaction mixture was heated at 90°C for 1 hour. After completing the reaction, the mixture was poured into cold water and extracted with ethyl acetate (20 mL x 2). The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure. The crude material was purified by column chromatography to provide 12.1 (0.130 g, 71.53%). MS (ES): m/z 560.5 [M+H] ⁺ .

Synthesis of compound I-12. A solution of 12.1 (0.130 g, 0.232 mmol, 1 equivalent) in TFA (6 mL) was heated at 70°C for 8 hours. After completion of the reaction, the reaction mixture was poured into cold water, neutralized with saturated sodium bicarbonate solution, and extracted with ethyl acetate (10 ml X 2). The solvent was removed under reduced pressure, and the resulting crude material was purified by column chromatography to obtain I-12 (0.030 g, 30.2%). MS(ES): m/z 428.4[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ ): δ 8.96 (s, 1H), 8.84 (s, 1H), 7.61-7.51 (m, 3H) ), 7.27-7.23(t, 2H), 6.97-6.94(d, 2H), 4.78-4.75(t, 2H), 4.46(s, 2H), 4.21-4.18(q, 1H), 3.60-3.50(m ,4H).

Example 13. Synthesis of compound 2-(2,6-difluorophenyl)-4-((4-methoxybenzyl)-amino)-6,7-dihydro-5H-pyrrolo[3,4 -d]pyrimidin-5-one, I-13

Synthesis of compound 13.1. At room temperature, to a solution of 1.1 (0.150g, 0.348mmol, 1.0 equivalent) in 1-butanol (2.0mL) was added 4-methoxybenzylamine (0.047g, 0.348mmol, 1.0 equivalent) and DIPEA ( 0.18ml, 1.04mmol, 3 equivalents). The reaction mixture was heated at 120°C for 3 hours. After completing the reaction, the mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude material was purified by column chromatography to obtain pure 13.1 (0.110 g, 59.5%), MS (ES): m/z 533.6 [M+H] ⁺ .

Synthesis of compound I-13. A solution of 13.1 (0.11 g, 0.206 mmol, 1.0 equivalent) in HBr/HOAc solution (33%, 3 ml) was stirred at room temperature for 1 hour. After completing the reaction, the mixture was poured into cold water, neutralized with NaHCO ₃ , and extracted with ethyl acetate (25 mL x 2). The solvent was removed under reduced pressure, and the resulting crude material was purified by column chromatography to obtain I-13 (0.045 g, 56.9%). MS(ES): m/z -383.4[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ ): δ 8.59 (s, 1H), 7.87 (m, 1H), 7.56 (m, 1H) , 7.29-7.21 (m, 4H), 6.86 (d, 2H), 4.60 (d, 2H), 4.36 (s, 2H), 3.71 (s, 3H).

Example 14. Synthesis of 2-(4-((2-(2,6-difluorophenyl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine- 4-yl)amino)phenyl)-N-ethyl-2-hydroxypropanamide, I-14

Synthesis of compound 14.2. At room temperature, to a solution of 14.1 (5.0g, 30.3mmol, 1.0 equivalent) in CH ₂ Cl ₂ (50mL) was added dropwise TMSCN (4.55ml, 36.34mmol, 1.2 equivalent) and TiCl ₄ (1.14g, 6.05mmol, 0.2 equivalent). The reaction was stirred at room temperature for 18 hours. The reaction mixture was quenched with ice cold water, and the _{product was extracted with CH 2} Cl ₂ (50 mL x 2). The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to obtain 14.2 (5.8 g, 99.69%). MS(ES): m/z has no ionization effect [M+H] ⁺ .

Synthesis of compound 14.3. To a solution of 14.2 (5.8 g, 30.2 mmol, 1.0 equivalent) in 1,4-dioxane (100 mL) was added concentrated HCl (50 mL). The reaction mixture was heated at 120°C for 5 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution. The organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure to obtain 14.3 (4.7g, 73.74%), which was used as is in the next step, MS(ES): m/z 210[M+H] ⁺ .

Synthesis of compound 14.4. To a solution of 14.3 (4.7g, 22.3mmol, 1.0 equivalent) in DMF (50mL) was added ethylamine (13.4ml, 26.7mmol, 1.2 equivalents), DIPEA (7.62ml, 44.5mmol, 2 equivalents) and HATU (10.16g) , 26.7mmol, 1.2 equivalents). The reaction mixture was stirred at room temperature for 1 hour. After completion, the mixture was diluted with EtOAc (100 mL) and washed with saturated NaHCO ₃ . The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain 14.4 (3.6 g, 67.9%). MS (ES): m/z 239.3 [M+H] ⁺ .

Synthesis of compound 14.5. Compound 14.4 (3.6 g, 15.1 mmol, 1.0 equivalent) was dissolved in MeOH (3 mL) and added to 10% Pd/C. Hydrogen gas was bubbled through the reaction mixture for 2 hours. After completing the reaction, the reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure to obtain compound 14.5 (3.12 g, 99.14%). MS (ES): m/z 209.2 [M+H] ⁺ .

Synthesis of compound 14.6. To a solution of 1.1 (0.3g, 0.69mmol, 1.0 equivalent) in 1-butanol (5mL) was added 14.5 (0.16g, 0.76mmol, 1.1 equivalent) and DIPEA (0.4ml, 2.08mmol, 3.0 equivalent). The reaction was stirred at 120°C for 2 hours. After completing the reaction, the mixture was poured into water, and the product was extracted with EtOAc (50 mL x 2). The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain 14.6 (0.35 g, 83.46%). MS (ES): m/z 604.5 [M+H] ⁺ .

Synthesis of compound I-14. A mixture of 14.6 (0.3 g, 0.49 mmol, 1.0 equivalent) and HBr/HOAc (5 mL) was stirred at room temperature for 1 hour. The reaction mixture was neutralized with saturated NaHCO ₃ and extracted with EtOAc (25 mL×2). The organic layers were combined, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain I-14 (0.17 g, 75.4%). MS(ES): m/z 454.7[M+H] ⁺ ; ¹ H NMR (DMSO-d ₆ , 400MHz): δ 9.05(s, 1H), 8.89(s, 1H), 7.83-7.86(t, 1H ),7.66-7.68(d,2H),7.58-7.60(m,1H),7.46-7.48(d,2H),7.25-7.29(m,2H),6.01(s,1H),4.47(s,2H) ), 3.03-3.08 (m, 2H), 1.58 (s, 3H), 0.94-0.98 (t, 3H).

Example 15. Synthesis of (S)-2-(4-((2-(2,6-difluorophenyl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4- d]Pyrimidine-4-yl)amino)phenyl)-N-ethyl-2-hydroxypropanamide, I-15

The compound I-14 was separated to obtain the compound I-15 . MS(ES): m/z 454.7[M+H] ⁺ , ¹ H NMR (400MHz, DMSO): δ 9.05(s,1H),8.89(s,1H),7.84-7.87(t,1H),7.66 -7.68(d,2H),7.58-7.62(m,1H),7.46-7.48(d,2H),7.24-7.29(t,2H),6.01(s,1H),4.47(s,2H),2.99 -3.08 (m, 2H), 1.58 (s, 3H), 0.94-0.98 (t, 3H).

Example 16. Synthesis of (R)-2-(4-((2-(2,6-difluorophenyl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4- d] Pyrimidine-4-yl)amino)phenyl)-N-ethyl-2-hydroxypropanamide. I-16

The compound I-14 was separated to obtain the compound I-16 . MS(ES): m/z 454.54[M+H] ⁺ , ¹ H NMR (400MHz, DMSO): δ 9.05 (s, 1H), 8.89 (s, 1H), 7.84-7.87 (t, 1H), 7.66 -7.68(d,2H),7.58-7.62(m,1H),7.46-7.48(d,2H),7.25-7.29(t,2H),6.01(s,1H),4.47(s,2H),3.01 -3.07 (m, 2H), 1.58 (s, 3H), 0.94-0.98 (t, 3H).

Example 17. Synthesis of 2-(2,6-difluorophenyl)-4-((2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-6-yl)amino)-6 ,7-Dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, I-17

Synthesis of compound 17.2. Slowly add palladium acetate to a solution of 17.1 (5.0 g, 39.0 mmol, 1.00 equivalent) in ethyl vinyl ether (11.25 g, 156.0 mmol, 4.0 equivalent). The reaction was stirred at room temperature for 20 hours. After the completion of the reaction, the resulting solution was filtered through Celite, washed with ethyl acetate, and the filtrate was distilled under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain pure 17.2 (1.0g, 12.92%). MS (ES): m/z 199.1 [M+H] ⁺ .

Synthesis of compound 17.4. To a solution of 17.3 (5.0 g, 54.6 mmol) in acetic acid (10 ml) was added sodium acetate (8.938 g, 109.0 mmol, 2.0 equivalents) and iodine monochloride (4.069 g, 65.5 mmol, 1.2 equivalents). The reaction mixture was heated at 70°C for 20 hours. After completing the reaction, the mixture was concentrated under reduced pressure, and the residue was diluted with water and basified with sodium bicarbonate solution. The compound was extracted in EtOAc and washed with brine. The organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure to obtain a crude material, which was purified by chromatography to obtain pure 17.4 (2.8 g, 28.2%), m/z = 255.1 [M+H] ⁺ .

Synthesis of compound 17.5. In a sealed tube, 17.4 (0.200 g, 0.78 mmol, 1 equivalent) and 17.2 (0.202 g, 1.02 mmol, 1.3 equivalent) were dissolved in DMF (5 mL). LiOH (0.095 g, 2.34 mmol, 3.0 equivalents) was added to the reaction mixture. The reaction mixture was degassed by argon for 10 to 15 minutes. Then PdCl ₂ (dppf) (0.063 g, 0.078 mmol, 0.1 equivalent) was added. The reaction mixture was further degassed by argon for 10 minutes. The reaction mixture was heated with stirring at 70°C for 16 hours. After the reaction was completed, water was added and the product was extracted with EtOAc (2 x 50ml), the organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain pure compound 17.5 (0.04g, 25.62%). MS (ES): m/z 199.2 [M+H] ⁺ .

Synthesis of compound 17.6. A solution of 17.5 (0.04g, 0.202mmol, 1.00 equivalent) in MeOH (1mL) and HCl (0.1ml) was heated to reflux overnight. After completing the reaction, the mixture was concentrated and _{basified with K 2} CO ₃ and extracted with EtOAc (2 x 50 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain pure compound 17.6 (0.025 g, 81.4%). MS (ES): m/z 153.5 [M+H] ⁺ .

Synthesis of compound 17.7. A solution of 17.6 (0.25 g, 1.10 mmol, 1.00 equivalent) and borane dimethyl sulfide composite solution (2.0 M in THF) (2 mL) in THF (1.0 mL) was heated at 68° C. for 3 hours. The reaction mixture was cooled to room temperature and poured into water; the product was extracted with EtOAc (50 mL x 3). The combined organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified with a silica gel column to obtain compound 17.7 (0.08 g, 31.58, MS (ES): m/z 155.6 [M+H] ⁺ .

Synthesis of compound 17.8. Stir at room temperature 17.7 (0.08g, 0.519mmol, 1.00 equivalent), di-tertiary butyl dicarbonate (0.191g, 0.876mmol, 1.5 equivalent) and DMAP (0.01g, 0.058mmol, 0.1 equivalent) contained in THF ( 10mL) solution for 3 hours. After completion, the reaction was diluted with water, and the product was extracted with ethyl acetate (25 mL×3) and washed with brine. The combined organic layer was dried and concentrated under vacuum. The crude material was purified by column chromatography to provide 17.8 (0.06g, 45.52%). MS (ES): m/z 255.1 [M+H] ⁺ .

Synthesis of compound 17.9. A solution of 17.8 (0.04 g, 0.157 mmol, 1.0 equivalent) in anhydrous THF (0.4 mL) was stirred for 15 minutes under argon at room temperature. _{Under argon purification, Pd 2} (dba) ₃ (0.014g, 0.0157mmol, 0.1 equivalent) and 2-biphenyl-di-tert-butylphosphine (0.01g, 0.031mmol, 0.2 equivalent) were added to the above reaction mixture, This lasted for 10 minutes, then LHMDS (7.8 mg, 0.047 mmol, 3.0 equivalents) was added. The reaction mixture was heated at 68°C for 1 hour. After completing the reaction, the reaction mixture was poured into water and extracted with EtOAc (25 mL×2). The organic layer was washed with brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by column chromatography to obtain 17.9 (0.028 g, 75.78%). MS (ES): m/z 254.1 [M+H] ⁺ .

Synthesis of compound 17.91. To a solution of 4.4 (0.08g, 0.18mmol, 1.0 equivalent) and 17.9 (0.043g, 0.186mmol, 1.0 equivalent) in 1,4-dioxane (2mL) was added K ₂ CO ₃ (0.051g, 0.580mmol, 3.0 equivalent). The reaction mixture was degassed under argon for 5 to 10 minutes, and Pd ₂ (dba) ₃ (0.016g, 0.018mmol, 0.1 equivalent) and Xantphos (0.01g, 0.018mmol, 0.2 equivalent) were added successively, and again under argon Degas under air for 5 minutes. The reaction mixture was heated at 90°C for 4 hours. After completing the reaction, the mixture was poured into water, and the product was extracted with EtOAc. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to obtain a crude material. The crude material was purified by column chromatography to obtain pure 133.91 (0.035g, 29.94%). MS(ES) : m/z 630.1 [M+H] ⁺ .

Synthesis of compound I-17. A solution of 17.91 (0.035g, 0.081mmol, 1.0 equivalent) in HBr/HOAc (33%, 1ml) was stirred at room temperature for 1 hour. After completing the reaction, the mixture was poured into cold water, neutralized with Na ₂ CO ₃ solution, and the product was extracted with ethyl acetate (25 mL x 3). The solvent was removed under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain pure I-17 (0.012g, 56.91%). MS(ES): m/z 468.1[M+H] ⁺ , ¹ H NMR (400MHz, DMSO-d ⁶ ): δ 9.39(s, 1H), 8.81(s, 1H), 8.48(s, 1H), 7.71(s, 1H), 7.60-7.55(m, 1H), 7.27-7.23(t, 2H), 6.55(s, 1H), 6.02(s, 1H), 4.39(s, 2H), 3.78-3.67( t, 2H), 2.92-2.88 (t, 2H).

Example 18. Synthesis of 2-(2,6-difluorophenyl)-4-((2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine-7 -Amino)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, I-18

Synthesis of compound 18.2. At 0°C, compound 18.1 (2.0g, 9.1mmol, 1.0 equivalent), 3-bromopropan-1-ol (1.9g, 13.6mmol, 1.5 equivalent) and PPh ₃ (3.59g, 13.6mmol, 1.5 equivalent) Dissolve in dry THF (40 mL) and stir for 1 hour. Diisopropyl azodicarboxylate (2.76 g, 13.6 mmol, 1.5 equivalents) was added at 0°C, and the reaction mixture was stirred for 3 hours. After the reaction was completed, water was added, and the product was extracted with EtOAc (100 mL x 2). The organic layer was separated, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain compound 18.2 (1.8 g, 57.97%). MS (ES): m/z = 339.1 [MH] ⁺ .

Synthesis of compound 18.3. To a solution of 18.2 (1.8 g, 5.3 mmol, 1.0 equivalent) in HOAc (18 mL) was added iron powder (1.18 g, 21.0 mmol, 4.0 equivalent). The reaction mixture was then heated at 90°C for 1 hour. After the completion of the reaction, EtOAc was added to the reaction mixture, and the reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain 18.3 . (1.2g, 73.1%), MS (ES): m/z 311.1 [M+H] ⁺ .

Synthesis 18.4. Add 18.3 (1.2g, 3.8mmol, 1.0 equivalent) to a cooled solution of NaH (60% in mineral oil, 0.31g, 7.7mmol, 2.0 equivalents) in DMF (6mL) at 0°C and keep it at room temperature Stir for 30 minutes. After the reaction was completed, saturated NH ₄ Cl solution was added to the reaction mixture, and extracted with EtOAc (200 mL x 2). The organic layer was washed with brine solution, dried over sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain compound 18.3 (0.4 g, 45.11%). MS (ES): m/z 227 [MH] ⁺ .

Synthesis of compound 18.5. A solution of 18.4 (0.24, 1.04 mmol, 1.0 equivalent) in ammonium hydroxide (10 mL) was heated in a hydrogenation vessel at 10 psi for 24 hours. After completing the reaction, the mixture was concentrated under reduced pressure to obtain a crude product, which was triturated with ether to obtain a pure 18.5 (0.09 g, 52.0%). MS (ES): m/z 166 [MH] ⁺ .

Synthesis of compound 18.6. At room temperature, to a solution of 18.5 (0.042g, 0.25mmol, 1.1 equivalent) in anhydrous 1,4-dioxane (1.0mL) was added 4.4 (0.1g, 0.23mmol, 1.0 equivalent), K ₂ CO ₃ (0.080 g, 0.04 mmol, 0.2 equivalent) and Xantphos (0.026 g, 0.04 mmol, 0.2 equivalent), and degas with argon for 15 minutes. _{Pd 2} (dba) ₃ (0.021 g, 0.02 mmol, 0.1 equivalent) was added to the above reaction mixture, and it was degassed again with argon for 15 minutes. The reaction mixture was heated at 110°C for 4 hours. After completing the reaction, the reaction mixture was poured into water and extracted with ethyl acetate (50 mL x 2). The organic layer was washed with saline solution. The organic layers were combined, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain a crude material, which was further purified by column chromatography to obtain pure 18.6 (0.052 g, 40.0%). MS (ES): m/z 560.2 [M+H] ⁺ .

Synthesis of compound I-18. A solution of 18.6 (0.055 g, 0.09 mmol, 1 equivalent) in HBr/HOAc (33%, 1 ml) was stirred at room temperature for 1 hour. After completing the reaction, the reaction mixture was poured into cold water, neutralized with sodium bicarbonate, and the product was extracted with EtOAc (25 mL x 2). The solvent was removed under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain pure I-18 (0.022 g, 57.8%). MS(ES): m/z 410.20[M+H] ⁺ , ¹ H NMR (400MHz, DMSO-d6): δ 9.48(s, 1H), 8.81(s, 1H), 8.35(s, 1H), 7.53 -7.57(t,1H),7.21-7.25(t,2H),7.11-7.13(d,1H),6.29-6.31(d,2H),4.38(s,2H),4.03-4.05(t,2H) , 3.23-3.29 (m, 2H), 1.89-1.92 (t, 2H).

Example 19. Synthesis of 4-(6-amino-1H-pyrrolo[2,3-b]pyridin-1-yl)-2-(2,6-difluorophenyl)-6,7-dihydro- 5H-pyrrolo[3,4-b]pyridin-5-one, I-19

Synthesis of compound 19.2. To a solution of 4.4 (0.050g, 0.116mmol, 1.0 equivalent) in 1,4-dioxane (1mL) was added 19.1 (0.023g, 0.174mmol, 1.5 equivalent) and K ₂ CO ₃ (0.04g, 0.29mmol, 2.5 equivalents). The reaction mixture was degassed for 10 minutes under an argon atmosphere, and then Pd ₂ (dba) ₃ (0.011 g, 0.012 mmol, 0.1 equivalent) and Xantphos (0.013 g, 0.023 mmol, 0.2 equivalent) were added, and degassed again for 5 minutes. Then the reaction was heated at 110°C for 2 hours. After completing the reaction, the reaction mixture was poured into water, and the product was extracted with EtOAc. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain pure 19.2 (0.040 g, 65.4%). MS (ES): m/z 528.5 [M+H] ⁺ .

Synthesis of compound I-19. Compound 19.2 (0.025 g, 0.0473 mmol, 1.0 equivalent) was dissolved in HBr/HOAc (1 mL) and stirred at room temperature for 1 hour. After completing the reaction, the mixture was poured into water, basified with saturated bicarbonate solution, and extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to obtain a crude material, which was purified to obtain pure I-19 (0.012 g, 67.2%). MS(ES): m/z 378.3[M+H] ⁺ , ¹ H NMR (DMSO-d ₆ , 400MHz): 8.95 (s, 1H), 8.27 (s, 1H), 6.49 (m, 3H), 7.30 (t, 2H), 6.43 (m, 2H), 5.86 (s, 2H), 4.55 (s, 2H).

Example 20. Synthesis of 4-((5-(6-azaspiro[2.5]oct-6-yl)pyridin-2-yl)amino)-2-(2,6-difluorophenyl)-6, 7-Dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, I-20

Synthesis of compound 20.2. To a solution of 20.1 (0.2g, 0.985mmol, 1.0 equivalent) in DMSO (3ml) was added TBAI (0.036g, 0.0985mmol, 0.1 equivalent), 6-azaspiro[2.5]octane (0.131g, 1.182mmol, 1.2 equivalents) and K ₂ CO ₃ (0.271 g, 1.97 mmol, 2 equivalents). The reaction mixture was heated in the microwave at 120°C for 4 hours. The reaction mixture was poured into water and extracted with EtOAc. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain a pure 20.2 (0.052 g, 22.70%). MS (ES): m/z 234.27 [M+H] ⁺ .

Synthesis of compound 20.3. Under a nitrogen atmosphere, to a solution of 20.2 (0.052 g, 0.222 mmol, 1.0 equivalent) in MeOH (5 mL) was added 10% Pd/C (0.0052 mg). It was _{purged with H 2} gas for 1 hour. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain a crude material 20.3 (0.040g), which was used as it is in the next step, MS(ES): m/z 204.3[M+H] ⁺ .

Synthesis of compound 20.4. To a solution of 4.4 (0.08g, 0.185mmol, 1.0 equivalent) in 1,4-dioxane (3mL) was added 20.3 (0.04g, 0.204mmol, 1.1 equivalent) and K ₂ CO ₃ (0.064g, 0.464mmol, 2.5 equivalents). The reaction mixture was degassed for 10 minutes under an argon atmosphere, and then Pd ₂ (dba) ₃ (0.0169 g, 0.0185 mmol, 0.1 equivalent) and Xantphos (0.021 g, 0.0371 mmol, 0.2 equivalent) were added, and degassed again for 5 minutes. The reaction was stirred at 110°C for 4 hours. After completing the reaction, the mixture was poured into water, and the product was extracted with EtOAc. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain a pure 20.4 (0.070 g, 63.10%). MS (ES): m/z 598.7 [M+H] ⁺ .

Synthesis of compound I-20. Compound 20.4 (0.07g, 0.117mmol, 1.0 equivalent) was dissolved in HBr/HOAc (2ml) and stirred at room temperature for 1 hour. After completing the reaction, the mixture was poured into water, basified with saturated bicarbonate solution, and extracted with EtOAc. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to obtain a crude material, which was purified to obtain pure I-20 (0.025 g, 47.7%). MS(ES): m/z 448.5[M+H] ⁺ ; ¹ H NMR (DMSO-d ₆ , 400MHz): 9.50(s, 1H), 8.80(s, 1H), 8.36(s, 1H), 8.04 (d, 1H), 7.57 (m, 1H), 7.45 (dd, 1H), 7.25 (m, 2H), 7.08 (d, 1H), 4.40 (s, 2H), 3.18 (t, 4H), 1.44 ( t, 4H), 0.32 (s, 4H).

Example 21. Synthesis of 4-((1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2-(2,6-difluoro-phenyl)-6,7-dihydro- 5H-pyrrolo[3,4-b]pyridin-5-one, I-21

Synthesis of compound 21.1. To a solution of 19.1 (0.5g, 3.75mmol, 1.0 equivalent) and NaOAc (0.49g, 6.00mmol, 1 equivalent) in acetic acid (5mL) was added phthalic anhydride (0.667g, 4.5mmol, 1.2 equivalent), and Stir at 120°C for 5 hours. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (20 mL X 3). The organic layers were combined, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain crude material. The crude material was stirred in saturated aqueous NaHCO ₃ solution, filtered and then dried to obtain pure 21.1 (0.400 g, 40.46%). MS (ES): m/z 264.3 [M+H] ⁺ .

Synthesis of compound 21.2. At 0℃, to a solution of 21.1 (0.450g, 1.70mmol, 1 equivalent) in THF (4.5mL) was added DMAP (0.020g, 0.17mmol, 0.1 equivalent) and di-tertiary butyl dicarbonate (0.447g). , 2.05 mmol, 1.2 equivalents). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (20 mL x 3). The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain 21.2 (0.50 g, 80.5%). MS (ES): m/z 364.3 [M+H] ⁺ .

Synthesis of compound 21.3. To a solution of 21.2 (0.300g, 0.825mmol, 1.0 equivalent) in EtOH (3mL) and CH ₂ Cl ₂ (1mL) was added N ₂ H ₄ -H ₂ O (99%) (0.040mL, 0.83mmol, 1.0 equivalent) ) And stirred at room temperature for 1 hour. The reaction mixture was poured into ice-cold saturated NaHCO ₃ solution (50 mL) and extracted with EtOAc (20 mL x 3). The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain 21.3 (0.15 g, 77.9%). MS (ES): m/z 234.3 [M+H] ⁺ .

Synthesis of compound 21.4. At room temperature and purging with argon, to a solution of 4.4 (0.10g, 0.23mmol, 1.0 equivalent) in anhydrous dioxane (5.0mL) was added 21.3 (0.081g, 0.35mmol, 1.5 equivalent) and K ₂ CO ₃ (0.095 g, 0.60 mmol, 3.0 equivalents) for 15 minutes. _{Under argon purge, Pd 2} (dba) ₃ (0.021 g, 0.023 mmol, 0.1 equivalent) and Xantphos (0.026 g, 0.046 mmol, 0.2 equivalent) were added to the above reaction mixture for 10 minutes. The reaction mixture was stirred at a temperature of 95°C for 3 to 4 hours. After completing the reaction, the mixture was poured into water and extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain a crude material. The crude material was purified by column chromatography to obtain a pure 21.4 (0.05g, 34.32%). MS (ES): m/z 628.6 [M+H] ⁺ .

Synthesis of compound I-21. A solution of 21.4 (0.025g) in HBr/HOAc solution (33%, 2ml) was stirred at room temperature for 1 hour. After completing the reaction, the mixture was poured into cold water, neutralized with NaHCO ₃ and extracted with ethyl acetate (50 ml X 2). At 45°C, the solvent was removed under reduced pressure. The crude material obtained was purified by column chromatography to obtain I-21 (0.010 g, 66.58%). MS(ES): m/z 378.35[M+H] ⁺ , ¹ H NMR (400MHz, DMSO-d ₆ ): δ 11.51 (s, 1H), 9.78 (s, 1H), 8.87 (s, 1H), 8.67(s,1H),7.94(d,1H),7.63-7.55(m,1H),7.30-7.26(m,3H), 6.82(d,1H), 6.39(s,1H), 4.43(s, 2H).

Example 22. Synthesis of 2-(2,6-difluorophenyl)-4-((2,3-dihydro-1H-pyrrolo[2,3-b]pyridine -6-yl)amino)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, I-22

Synthesis of compound 22.1. Under a nitrogen atmosphere, to a solution of 21.4 (0.10g, 0.159mmol, 1.0 equivalent) in EtOH (10.0mL) and 1,2-dimethoxyethane (10.0mL) was added 10% Pd/C (0.010mg ). The suspension was purged with hydrogen for 12 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain crude material 22.1 (0.090g, 89.72%), which was used as is in the next step, MS(ES): m/z 630.7[M+ H] ⁺ .

Synthesis of compound I-22. A solution of 22.1 (0.09g) in HBr/HOAc solution (33%, 2ml) was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was poured into cold water, neutralized with NaHCO ₃ , and the product was extracted with EtOAc (50 mL×2). The solvent was concentrated under reduced pressure to obtain a crude material, _{which was triturated with Et 2} O (2.0 mL) and MeOH (0.2 mL) to obtain I-22 . (0.05g, 92.2%). MS(ES): m/z 380.4[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ ): δ 9.46(s, 1H), 8.81(s, 1H), 8.34(s, 1H), 7.56 (t, 1H), 7.27-7.23 (m, 3H), 6.52 (s, 1H), 6.12 (d, 1H), 4.39 (s, 2H), 3.46 (t, 2H), 2.91 (t, 2H) .

Example 23. Synthesis of 2-(2,6-difluorophenyl)-4-((3,3-dimethyl-2,3-dihydrobenzofuran-6-yl)amino)-6,7 -Dihydro-5H-pyrrolo[3,4-d]pyrimidin-5-one, I-23

Synthesis of compound 23.2. Under an argon atmosphere at 0° C., to a solution of 23.1 (0.97 g, 4.1 mmol, 1.0 equivalent) in anhydrous CH ₂ Cl ₂ (6.0 mL) was added anhydrous AlCl ₃ (1.66 g, 12.5 mmol, 3.0 equivalent). The reaction mixture was stirred at 50°C for 16 hours. After completing the reaction, the mixture was poured into dilute HCl to adjust the pH to 4, and extracted with CH ₂ Cl ₂ . The organic layer was washed with brine and dried over sodium sulfate. The organic layer was concentrated under reduced pressure, and the crude material was purified by column chromatography to obtain pure 23.2 (0.76 g, 83.39%). MS (ES): m/z 219.1 [M+H] ⁺ .

Synthesis of compound 23.3. At room temperature, to a solution of 23.2 (0.76 g, 3.57 mmol, 1.0 equivalent) in acetone (8 mL) was added K ₂ CO ₃ (1.20 g, 8.71 mmol, 2.5 equivalents) and NaI (0.575 g, 3.83 mmol, 1.1 Equivalent) and stirred for 20 minutes. To the mixture was added 3-bromo-2-methylpropane (0.611 g, 4.53 mmol, 1.3 equivalents), and the reaction was heated at reflux temperature for 2 hours. After completing the reaction, the mixture was diluted with water and extracted with EtOAc. The organic layer was dried over sodium sulfate and concentrated under reduced pressure at 45°C. The crude material was purified by column chromatography to provide 23.3 (0.60 g, 63.25%). MS (ES): m/z =273.1 [M+H] ⁺ .

Synthesis of compound 23.4. To a solution of 23.3 (0.6g, 2.20mmol, 1.0 equivalent) in anhydrous DMF (15.0ml) was added Et ₃ NI (0.38g, 2.4mmol, 1.09 equivalent), sodium formate (0.156g, 2.40mmol, 1.09 equivalent) and NaOAc (0.44g, 5.51mmol, 2.5 equivalents). The reaction mixture was degassed for 10 minutes, palladium acetate (0.048 g, 0.22 mmol, 0.1 equivalent) was added, and the reaction mixture was degassed again for 10 minutes. The reaction mixture was heated at 70°C overnight. After completing the reaction, the mixture was poured into cold water, and the product was extracted with EtOAc. The organic layer was washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure, and the crude material was purified by column chromatography to obtain a pure 23.4 (0.34g, 79.8%). MS (ES): m/z 194.3 [M+H] ⁺ .

Synthesis of compound 23.5. Under a nitrogen atmosphere, to a suspension of Pd/C (0.034 g) in MeOH (10 mL) was added 23.4 (0.340 g, 1.76 mmol, 1.0 equivalent). The above reaction mixture was purged _{with H 2} (gas) at room temperature for 1 hour. After completing the reaction, the reaction mixture was filtered through Celite. The solvent was removed under reduced pressure to obtain 23.5 (0.250 g, 87.0%). MS (ES): m/z 164.4 [M+H] ⁺ .

Synthesis 23.6. At room temperature, to a solution of 1.1 in DMSO (5.0 mL) was added 24.5 (0.075 g, 0.46 mmol, 1.0 equivalent) and DIPEA (0.149 mg, 1.16 mmol, 2.5 equivalent). The reaction was heated at 70°C for 30 minutes. After completing the reaction, the mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude material was purified by column chromatography to provide a purity of 23.6 (0.151 g, 58.37%). MS (ES): m/z 559.6 [M+H] ⁺ .

Synthesis of compound I-23. A solution of 23.6 (0.151 g) in TFA (6 mL) was heated at 70°C for 8 hours. After completing the reaction, the mixture was concentrated under reduced pressure at 45°C. The resulting residue was poured into cold water, and neutralized with NaHCO _3, and extracted with EtOAc. The solvent was removed under reduced pressure to obtain a crude material, which was purified by preparative TLC to obtain pure I-23 (34 mg, 30.8%). MS(ES): m/z 409.4[M+H] ⁺ , ¹ H NMR (400MHz, DMSO-d ₆ ): δ 8.99(s,1H),8.89(s,1H),7.62-7.58(m,1H ),7.40(s,1H),7.30-7.26(t,2H),7.17-7.15(d,1H),7.10-7.08(s,1H),4.47(s,2H),4.21(s,2H), 1.27(s, 6H).

Example 24. Synthesis of compound 4-((5-(2-oxa-7-azaspiro[3.5]non-7-yl)pyridine-2- Yl)amino)-2-(2,6-difluorophenyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, I-24

Synthesis of compound 24.1. To a solution of 20.1 (0.6g, 2.95mmol, 1.0 equivalent) in 1,4-dioxane (10ml) was added 2-oxa-7-azaspiro[3.5]nonane (0.641g, 2.95mmol, 1.0 Equivalent) and K ₂ CO ₃ (1.2 g, 8.86 mmol, 3.0 equivalent). The reaction mixture was degassed with argon for 10 minutes, then Pd ₂ (dba) ₃ (0.063 g, 0.29 mmol, 0.1 equivalent) and Xantphos (0.341 g, 0.59 mmol, 0.2 equivalent) were added, and degassed again for 5 minutes. The reaction was stirred at 120°C for 4 hours. After completing the reaction, the reaction mixture was poured into water, and the product was extracted with EtOAc. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to obtain a crude material, which was purified to obtain pure 24.1 (0.210 g, 28.5%). MS (ES): m/z 250.2 [M+H] ⁺ .

Synthesis of compound 24.2. Under a nitrogen atmosphere, to a solution of 24.1 (0.210 g, 0.84 mmol, 1.0 equivalent) in MeOH (5 mL) was added 10% Pd/C (0.050 g). It was _{purged with H 2} gas for 1 hour. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain a crude substance 24.2 (0.130 g, 70.37%), which was used as it is in the next step, MS (ES): m/z 220.2 [M+ H] ⁺ .

Synthesis of compound I-24. To a solution of 24.3 (0.050g, 0.15mmol, 1.0 equivalent) in 1,4-dioxane (3mL) was added 1.2 (0.027g, 0.12mmol, 0.8 equivalent) and sodium tert-butoxide (0.029g, 0.30mmol) , 2.0 equivalent). Under an argon atmosphere so that the reaction mixture was degassed for 10 minutes and then (2-dicyclohexylphosphino-2 ', 4', 6 '- triisopropyl-1,1' - biphenyl) [2- ( 2 '- amino-1,1' - biphenyl)] palladium (II) chloride (0.022g, 0.030mmol, 0.2 equiv), degassed again for 5 minutes. The reaction was stirred at 100°C for 8 hours. After completing the reaction, the mixture was poured into water, and the product was extracted with EtOAc. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain pure I-24 (0.011 g, 10.4%). MS (ES): m/z 464.4 [M+H] ⁺ . 1H NMR (CDCl ₃ , 400MHz): 9.41 (s, 1H), 8.54 (s, 1H), 8.04 (s, 1H), 7.43-7.30 (m, 2H), 7.06-7.01 (m, 2H), 6.92 6.90 (d, 1H), 4.54 (s, 2H), 4.49 (s, 4H), 3.09-3.06 (t, 4H), 2.05-2.03 (t, 4H).

Example 25. Synthesis of 4-((5-(1-oxa-7-azaspiro[3.5]non-7-yl)pyridin-2-yl)amino)-2-(2,6-difluorobenzene Yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, I-25

Synthesis of compound 25.2. To a solution of trimethylsulfonium iodide (22.09 g, 100.4 mmol, 4.0 equivalents) in tertiary butanol (150 mL) was added potassium tertiary butoxide (11.24 g, 100.4 mmol, 4.0 equivalents). The reaction was stirred at 50°C for 1 hour. Then 25.1 (5g, 25mmol, 1 equivalent) was added at 50°C and stirred for 2 days. After completing the reaction, the mixture was concentrated under reduced pressure. To the reaction mixture was added water and the product extracted with Et ₂ O. The organic layers were combined, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain a crude material, which was purified by trituration in hexane to obtain pure 25.2 (3.6 g, 63.11%). MS (ES): m/z 227.30 [M+H] ⁺ .

Synthesis of compound 25.3. To compound 25.2 (3.6 g, 15.78 mmol, 1.0 equivalent) was added TFA. The reaction was stirred for 2 hours. After completing the reaction, the mixture was concentrated under reduced pressure. Amberlyst resin was used to neutralize the reaction mixture in methanol. The reaction mixture was concentrated under reduced pressure to obtain crude material 25.3 (2.0 g, 99.3%), which was used as it is in the next step, MS (ES): m/z 127.19 [M+H] ⁺ .

Synthesis of compound 25.4. To a solution of 20.1 (2.0g, 9.85mmol, 1 equivalent) in DMSO (18ml) was added compound 25.3 (1.87g, 14.77mmol, 1.5 equivalent), tetrabutylammonium iodide (0.363g, 0.98mmol, 0.1 equivalent) And K ₂ CO ₃ (4.078 g, 29.55 mmol, 3.0 equivalents). The reaction mixture was heated at 90°C for 2 hours. After completing the reaction, the mixture was poured into water to obtain a solid product. The product was extracted with EtOAc. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain 25.4 (0.37 g, 10.1%). MS (ES): m/z 249.27 [M+H] ⁺ .

Synthesis of compound 199.5. Under a nitrogen atmosphere, to a solution of 199.4 (0.370 g, 1.48 mmol, 1.0 equivalent) in MeOH (15 mL) was added 10% Pd/C (0.060 g). It was purged with hydrogen for 1 hour. The reaction mixture was filtered through Celite, and the resulting filtrate was concentrated under reduced pressure to obtain a crude substance 199.5 (0.263 g, 98.88%), which was used as it is in the next step. MS (ES): m/z 219.29 [M+H] ⁺ .

Synthesis of compound 24.3. Compound 4.4 (1.0 g, 2.32 mmol, 1.0 equivalent) was dissolved in HBr/HOAc (10 ml) and stirred at room temperature for 4 hours. After completing the reaction, the mixture was poured into water, and basified with saturated bicarbonate solution, and extracted with EtOAc. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain pure 24.3 (0.630 g, 83.49%). MS (ES): m/z 325.11 [M+H] ⁺ .

Synthesis of compound I-25. To a solution of compound 24.3 (0.250g, 0.768mmol, 1.0 equivalent) in 1,4-dioxane was added compound 25.5 (0.168g, 0.768mmol, 1.0 equivalent) and K ₃ PO ₄ (0.326g, 1.53mmol, 2.0 equivalent). The reaction mixture was degassed for 15 minutes. The pre-catalyst Xantphos (0.111 g, 0.153 mmol, 0.2 equivalent) was added to the reaction mixture, and the reaction was further degassed for 10 minutes. The reaction mixture was heated at 100°C for 20 minutes. After completing the reaction, the mixture was poured into water, and the product was extracted with EtOAc. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography and preparative HPLC to obtain I-25 (0.007 g, 2.92%). MS(ES): m/z 463.49[M+H] ⁺ , ¹ H NMR(DMSO-d6,400MHz): 9.48(s,1H), 8.80(s,1H), 8.36(s,1H), 8.02 8.01(d,2H),7.59-7.54(m,1H),7.46-7.43(dd,1H),7.27-7.23(t,3H),7.10-7.08(d,1H), 5.50(s,1H), 4.48-4.46 (t, 1H), 4.40 (s, 2H), 3.60 (s, 2H), 3.52-3.44 (m, 2H), 3.31-3.28 (m, 2H), 2.16 (s, 4H).

Example 26. Synthesis of 2-(4-((2-(2,6-difluorophenyl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine- 4-yl)amino)phenyl)-N-ethyl-4,4,4-trifluoro-2-hydroxybutyramide, I-26

Synthesis of compound 26.1. To 1.1 (0.06g, 0.137mmol, 1.0 equivalent) in butanol (3mL) was added 2-(4-aminophenyl)-N-ethyl-3-in complex with 113,311-prop-1-yne Fluoro-2-hydroxypropanamide (1:1) (0.038g, 0.137mmol, 1.0 equivalent) and DIPEA (0.07ml, 0.411mmol, 3.0 equivalent). The reaction was heated at 85°C for 2 hours. After completing the reaction, the mixture was poured into water, and the product was extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to obtain the crude material 26.1 , which was used in the next step without further purification. 1.1 (0.07g, 64.3%). MS (ES): m/z 671.6 [M+H] ⁺ .

Synthesis of compound I-26. A solution of 26.1 (0.12 g, 0.214 mmol, 1.0 equivalent) in HBr/HOAc (3 mL) was stirred at room temperature for 2 hours. After completion, the reaction was quenched with water and extracted with EtOAc. The organic layer was washed with saturated NaHCO _{3 solution.} The combined organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain I-26 (0.053 g, 97.5%). MS (ES): m/z 521.6 [M+H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ 8.82 (s, 1H), 7.83-7.81 (d, 2H), 7.60-7.57 (d, 2H), 7.48-7.41 (m, 1H), 7.08-7.02 (m , 2H), 6.82-6.79 (m, 1H), 6.25 (s, 1H), 4.56 (s, 2H), 3.51-3.16 (m, 4H), 1.14-1.11 (t, 3H).

Example 27. Synthesis of (S)-2-(4-((2-(2,6-difluorophenyl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4- d]Pyrimidine-4-yl)amino)phenyl)-N-ethyl-4,4,4-trifluoro-2-hydroxybutyramide, I-27

The compound I-26 was separated to obtain the compound I-27 . MS(ES): m/z 521.3[M+H] ⁺ , ¹ H NMR (400MHz, CDCl ₃ ): δ 8.78 (s, 1H), 7.84-7.81 (d, 2H), 7.59-7.57 (d, 2H) ),7.45-7.42(m,1H),7.07-7.03(m,2H),6.83-6.80(m,1H),6.33(s,1H),4.54(s,2H),3.44-3.17(m,3H) ), 2.87-2.81 (m, 1H), 1.14-1.11 (t, 3H).

Example 28. Synthesis of (R)-2-(4-((2-(2,6-difluorophenyl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4- d]Pyrimidine-4-yl)amino)phenyl)-N-ethyl-4,4,4-trifluoro-2-hydroxybutyramide, I-28

The compound I-26 was separated to obtain the compound I-28 . MS(ES): m/z 521.3[M+H] ⁺ , ¹ H NMR (400MHz, CDCl ₃ ): δ 8.78 (s, 1H), 7.84-7.81 (d, 2H), 7.59-7.57 (d, 2H) ),7.45-7.42(m,1H),7.07-7.03(m,2H),6.83-6.80(m,1H),6.33(s,1H),4.54(s,2H),3.44-3.17(m,3H) ), 2.87-2.81 (m, 1H), 1.14-1.11 (t, H).

Example 29. Synthesis of 2-(2,6-difluorophenyl)-4-((4-(2,2,2-trifluoro-1-hydroxy-ethyl)phenyl)amino)-6,7 -Dihydro-5H-pyrrolo[3,4-d]pyrimidin-5-one, I-29

Synthesis of compound 29.2. At 0°C, to a solution of 29.1 (1 g, 6.6 mmol, 1.0 equivalent) in THF (3 ml) was added trimethyl(trifluoromethyl)silane (1.41 g, 9.9 mmol, 1.5 equivalent). Tetramethylammonium fluoride (0.132ml, 0.13mmol, 0.02 equivalent) was added at 0°C and stirred for 10 minutes, and then stirred at room temperature for 2 hours. The reaction mixture was poured into 3N HCl, the product was extracted with CH ₂ and ₂ Cl. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain pure 29.2 (1.1 g, 75.17%). MS (ES): m/z 221.14 [M+H] ⁺ .

Synthesis of compound 29.3. Under a nitrogen atmosphere, to a solution of 29.2 (1.1 g, 5.0 mmol, 1.0 equivalent) in MeOH (10 mL) was added 10% Pd/C (0.2 g). It was purged with hydrogen for 1 hour. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain a crude material 29.3 (0.820 g, 86.2%), which was used as it is in the next step, MS (ES): m/z 191.15 [M+ H] ⁺ .

Synthesis of compound 29.4. To a solution of 1.1 (0.300g, 0.697mmol, 1.0 equivalent) in n-butanol (4ml) was added 29.3 (0.146g, 0.767mmol, 1.1 equivalent) and DIPEA (0.27g, 2.093mmol, 3.0 equivalent). The reaction was stirred at 110°C for 2 hours. After completing the reaction, the mixture was poured into water, and the product was extracted with EtOAc. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain 29.4 (0.320 g, 78.53%). MS (ES): m/z 586.52 [M+H] ⁺ .

Synthesis of compound I-29. Compound 29.4 (0.320 g, 0.545 mmol, 1.0 equivalent) was dissolved in HBr/HOAc (5 ml) and stirred at room temperature for 2 hours. After completing the reaction, the mixture was poured into water, _{basified with saturated NaHCO 3} solution and extracted with EtOAc. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain I-26 (0.125 g, 52.52%). MS(ES): m/z 436.34[M+H] ⁺ , ¹ H NMR (MeOD, 400MHz): 7.87-7.85 (d, 2H), 7.60-7.52 (m, 1H), 7.50-7.48 (d, 2H) ), 7.18-7.14 (m, 2H), 5.05-4.99 (s, 2H), 4.52 (s, 1H).

Example 30. Synthesis of (S)-2-(2,6-difluorophenyl)-4-((4-(2,2,2-trifluoro-1-hydroxyethyl)phenyl)amino)- 6,7-Dihydro-5H-pyrrolo[3,4-d]pyrimidin-5-one, I-30

Compound I-30 was obtained by isolating the compound I-29 in parallel. MS(ES): m/z 436.34[M+H] ⁺ , ¹ H NMR (400MHz, MeOD): δ 7.87-7.85 (d, 2H), 7.58-7.53 (m, 3H), 7.50-7.48 (d, 2H), 7.18-7.14 (m, 2H), 4.52 (s, 1H).

Example 31. Synthesis of (R)-2-(2,6-difluorophenyl)-4-((4-(2,2,2-trifluoro-1-hydroxyethyl)phenyl)amino)- 6,7-Dihydro-5H-pyrrolo[3,4-d]pyrimidin-5-one, I-31

Compound I-31 was obtained by isolating compound I-29 by hand. MS(ES): m/z 436.34[M+H] ⁺ , ¹ H NMR (400MHz, MeOD): δ 7.87-7.85 (d, 2H), 7.60-7.53 (m, 1H), 7.50-7.48 (d, 2H), 7.18-7.14 (m, 2H), 4.64 (s, 2H), 4.52 (s, 1H).

Example 32. Synthesis of 2-amino-2-(4-((2-(2,6-difluorophenyl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4 -d]pyrimidin-4-yl)amino)phenyl)propionic acid, 1-32

Synthesis of compound 32.1. To 1.1 (0.073g, 0.170mmol, 1.0 equivalent) in butanol (5mL) was added 2-(4-aminophenyl)-2-((tertiary butoxycarbonyl)-amino)propionic acid Methyl ester (0.050g, 0.170mmol, 1.0 equivalent) and DIPEA (0.09ml, 0.510mmol, 3.0 equivalent). The reaction was stirred at 100°C for 2 hours. After completing the reaction, the mixture was poured into water, and the product was extracted with EtOAc. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to obtain crude material 32.1 (0.070 g, 60.04%), which was used in the next step without further purification. MS (ES): m/z 690.72 [M+H] ⁺ .

Synthesis of compound 32.2. A solution of 32.1 (0.070 g, 0.106 mmol, 1.0 equivalent) in HBr/HOAc (3 mL) was stirred at room temperature for 2 hours. After completion, water was added and the product was extracted with EtOAc. The organic layer was washed with saturated NaHCO _{3 solution.} The combined organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain 32.2 (0.030 g, 67.27%). MS (ES): m/z 440.42 [M+H] ⁺ .

Synthesis of compound I-32. Compound 32.2 (0.030 g, 0.068 mmol, 1.0 equivalent) was dissolved in MeOH (2 ml). Add 2N NaOH (0.090ml, 0.204mmol, 3.0 equivalents) and stir at room temperature for 1 hour. After completing the reaction, the mixture was concentrated under reduced pressure. The crude compound was purified by preparative HPLC to obtain pure I-32 (0.008 g, 24.4%). MS(ES): m/z 425.40[M+H] ⁺ , ¹ H NMR (MeOD, 400MHz): 7.88-7.85 (m, 2H), 7.58-7.53 (m, 3H), 7.16-7.12 (m, 2H ), 4.51(s, 2H), 1.88(s, 3H).

Example 33. Synthesis of 2-(2,6-difluorophenyl)-4-((4-(1,1,1-trifluoro-2-hydroxy-prop-2-yl)phenyl)amino)- 6,7-Dihydro-5H-pyrrolo[3,4-d]pyrimidin-5-one, I-33

Synthesis of compound 33.2. To a solution of 33.1 (1 g, 6 mmol, 1.0 equivalent) in THF (15 ml) was added trimethyl(trifluoromethyl)silane (1.3 g, 9 mmol, 1.5 equivalent) and cooled at 0°C. Tetrabutylammonium fluoride (0.132 ml, 0.13 mmol, 0.02 equivalent) was added at 0°C and stirred for 10 minutes, and then stirred at room temperature for 2 hours. The reaction mixture was poured into 3N HCl, and the product was extracted with EtOAc. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain pure 33.2 (1 g, 70.2%). MS (ES): m/z 235.16 [M+H] ⁺ .

Synthesis of compound 33.3. Under a nitrogen atmosphere, to a solution of 33.2 (0.3 g, 1.2 mmol, 1.0 equivalent) in MeOH (10 mL) was added 10% Pd/C (0.2 g). It was purged with hydrogen for 1 hour. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain crude material 33.3 (0.250g, 95.51%), which was used as it is in the next step, MS(ES): m/z 205.18[M+ H] ⁺ .

Synthesis of compound 33.4. To a solution of 1.1 (0.100g, 0.23mmol, 1.0 equivalent) in n-butanol (5ml) was added 33.3 (0.047g, 0.23mmol, 1 equivalent) and DIPEA (0.089g, 0.69mmol, 3.0 equivalent). The reaction mixture was stirred at 90°C for 3 hours. After the reaction was completed, the n-butanol was removed under high vacuum to obtain crude material 33.4 (0.100 g, 71.99%). MS (ES): m/z 600.18 [M+H] ⁺ .

Synthesis of compound I-33. Compound 33.4 (0.100g, 0.166mmol, 1.0 equivalent) was dissolved in HBr/HOAc (3ml) and stirred at room temperature for 1 hour. After completing the reaction, the mixture was poured into water and _{basified with saturated NaHCO 3} and the product was extracted with EtOAc. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain pure I-33 (0.050 g, 66.7%). MS(ES): m/z 450.37[M+H] ⁺ , ¹ H NMR (DMSO-d ₆ , 400MHz): 9.13(s,1H), 8.92(s,1H), 7.80-7.78(d,2H) , 7.56-7.54 (m, 3H), 7.29-7.27 (m, 2H), 6.55 (d, 1H), 4.49 (s, 2H), 1.67 (s, 3H).

Example 34. Synthesis of (S)-2-(2,6-difluorophenyl)-4-((4-(1,1,1-trifluoro-2-hydroxy-prop-2-yl)phenyl) Amino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-5-one, I-34

Compound I-34 was prepared by isolating compound I-33 . MS(ES): m/z 450.37[M+H] ⁺ , ¹ H NMR (400MHz, MeOD): δ 7.85-7.80 (m, 2H), 7.63-7.52 (m, 3H), 7.18-7.13 (m, 2H), 4.52(s, 2H), 1.73(s, 3H).

Example 35. Synthesis of (R)-2-(2,6-difluorophenyl)-4-((4-(1,1,1-trifluoro-2-hydroxy-prop-2-yl)phenyl) Amino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-5-one, I-35

Compound I-35 was prepared by isolating compound I-33 . MS (ES): m/z 450.37 [M+H] ⁺ , ¹ H NMR (400MHz, MeOD): δ 7.85-7.83 (m, 2H), 7.61-7.54 (m, 3H), 7.18-7.14 (m, 2H), 4.52(s, 2H), 1.73(s, 3H).

Example 36. Synthesis of 4-((5-(1-oxa-6-azaspiro[3.5]non-6-yl)pyridin-2-yl)amino)-2-(2,6-difluorobenzene Yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, 1-36

Synthesis of compound 36.1. To a solution of 20.1 (0.400g, 1.97mmol, 1.0 equivalent) in 1,4-dioxane (10mL) was added 1-oxa-6-azaspiro[3.5]nonane (0.406g, 2.36mmol, 1.2 Equivalent) and Cs ₂ CO ₃ (1.92 g, 5.91 mmol, 3.0 equivalent). Degas the reaction mixture with argon for 10 minutes, then add Pd ₂ (dba) ₃ (0.180 g, 0.197 mmol, 0.1 equivalent) and 2-dicyclohexylphosphino-2 ' -(N,N-dimethylamine) Base) biphenyl (0.154 g, 0.394 mmol, 0.2 equivalent) and degas again for 5 minutes. The reaction was stirred at 110°C for 4 hours. After completing the reaction, the mixture was poured into water, and the product was extracted with EtOAc. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain 36.1 (0.36 g, 73.3%). MS (ES): m/z 250.6 [M+H] ⁺ .

Synthesis of compound 36.2. Under a nitrogen atmosphere, to a solution of 36.1 (0.360 g, 1.44 mmol, 1.0 equivalent) in MeOH (5 mL) was added 10% Pd/C (0.350 g). It was purged with hydrogen for 1 hour. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain a crude substance 36.2 (0.300g, 94.73%), which was used in the next step as it is, MS(ES): m/z 220.23[M+ H] ⁺ .

Synthesis of compound I-36. To a solution of 24.3 (0.400g, 1.23mmol, 1.0 equivalent) in 1,4-dioxane (3mL) was added 36.2 (0.269g, 1.23mmol, 1.0 equivalent) and K ₃ PO ₄ (0.52g, 2.46mmol, 2.0 equivalent). The reaction mixture with argon and degassed for 10 minutes and then (2-dicyclohexylphosphino-2 ', 4', 6 '- triisopropyl-1,1' - biphenyl) [2- (2- Aminoethyl)phenyl)]palladium(II) chloride (0.182g, 0.25mmol, 0.2eq), and degas again for 5 minutes. Then, the reaction was stirred at 100°C for 1 hour. After completing the reaction, the mixture was poured into water, and the product was extracted with EtOAc. The organic layers were combined, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain I-36 (0.163 g, 28.6%). MS (ES): m/z 463.6 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ): δ 9.51 (s, 1H), 8.81 (s, 1H), 8.39 (s, 1H), 8.09 (s, 1H), 7.64-7.49 (m, 2H), 7.34-7.23 (m, 2H), 7.10-7.08 (d, 1H), 4.48-4.39 (m, 1H), 4.38 (s, 2H), 3.43-3.40 (m, 1H), 3.12-3.01 (m, 2H) ), 2.90-2.86 (m, 1H), 2.43-2.28 (m, 3H), 1.87-1.83 (m, 1H), 1.73-1.62 (m, 2H), 1.56-1.50 (m, 1H).

Example 37. Synthesis of (R)-4-((5-(1-oxa-6-azaspiro[3.5]non-6-yl)pyridin-2-yl)amino)-2-(2,6 -Difluorophenyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, I-37

Compound I-36 by chiral separation performed to obtain compound I-37. MS(ES): m/z 463.3[M+H] ⁺ , ¹ H NMR (400MHz, MeOD): δ 8.45 (s, 1H), 8.10 (s, 1H), 7.56-7.50 (m, 2H), 7.16 -7.12(m,2H),7.06-7.04(d,1H),4.65-4.55(m,2H),4.47(s,2H),3.33-3.31(m,2H),3.09-3.07(m,2H) , 2.55-2.45 (m, 2H), 1.91-1.86 (m, 2H), 1.70-1.66 (m, 2H).

Example 38. Synthesis of (S)-4-((5-(1-oxa-6-azaspiro[3.5]non-6-yl)pyridin-2-yl)amino)-2-(2,6 -Difluorophenyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, I-38

Compound I-36 by chiral separation performed to obtain compound I-38. MS(ES): m/z 463.3[M+H] ⁺ , ¹ H NMR (400MHz, MeOD): δ 8.45 (s, 1H), 8.10 (s, 1H), 7.56-7.50 (m, 2H), 7.16 -7.12(m,2H),7.06-7.04(d,1H),4.65-4.55(m,2H),4.47(s,2H),3.33-3.31(m,2H),3.09-3.07(m,2H) , 2.55-2.45 (m, 2H), 1.91-1.86 (m, 2H), 1.70-1.66 (m, 2H).

Example 39. Synthesis of 2-(4-((2-(2,6-difluorophenyl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine- 4-yl)amino)phenyl)-2,4-dimethyl-2H-benzo[b][1,4]oxazine-3(4H)-one, I-39

Synthesis of compound 39.2. To a solution of 39.1 (5.0 g, 23.92 mmol, 1.0 equivalent) in THF (50 ml) was added MeI (3.73 g, 26.31 mmol, 1.1 equivalent) and 18-crown-6 (1.57 g, 59.80 mmol, 0.25 equivalent). The reaction mixture was cooled to -78°C and potassium tertiary butoxide (2.94 g, 26.31 mmol, 1.1 equivalents) was added. The reaction was stirred at room temperature for 6 hours. After completing the reaction, NH ₄ Cl was added at -78°C. The product was extracted with EtOAc. The organic layers were combined, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain 39.2 (4.5 g, 84.34%). MS (ES): m/z 223.23 [M+H] ⁺ .

Synthesis of compound 39.3. To a solution of compound 39.2 (4.5 g, 20.17 mmol, 1.0 equivalent) in ethanol (40 ml) was added NaOH (1.614 g, 40.35 mmol, 2 equivalents) and water (10 ml). The reaction was stirred at room temperature for 2 hours. After completing the reaction, the solvent was evaporated under reduced pressure, and water was added. The reaction mixture was acidified by adding dilute HCl. The product was extracted with ethyl acetate. The organic layers were combined, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain 39.3 (3.1 g, 78.8%). MS (ES): m/z 195.17 [M+H] ⁺ .

Synthesis of compound 39.4. To a solution of 2-fluoro-N-methylaniline (1.98 g, 15.89 mmol, 1 equivalent) in CH ₂ Cl ₂ (50 ml) was added compound 39.3 (3.1 g, 15.8 mmol, 1 equivalent). Additional DMAP (0.386 g, 3.168 mmol, 0.2 equiv) was added and the reaction was allowed to cool at 0°C. Dicyclohexylcarbodiimide (3.91 g, 19.00 mmol, 1.2 equivalents) was added at 0°C and the reaction was stirred at room temperature for 24 hours. After completing the reaction, the mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain pure 39.4 (0.330 g, 10.76%). MS (ES): m/z 302.31 [M+H] ⁺ .

Synthesis of compound 39.5. To a solution of compound 39.4 (0.280g, 0.927mmol, 1 equivalent) in DMF (10ml) was added copper(II) chloride (0.273g, 2.039mmol, 2.2 equivalents) and sodium tert-butoxide (0.45g, 4.64mmol) , 5.0 equivalents). The reaction was stirred at 80°C for 24 hours. After completing the reaction, the mixture was poured into water, and a brine solution was added thereto. The product was extracted with EtOAc. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to obtain a crude material, which was further purified by column chromatography to obtain pure 39.5 (0.069 g, 24.9%). MS (ES): m/z 298.30 [M+H] ⁺ .

Synthesis of compound 39.6. To a suspension of Pd/C (20 mg) in methanol (2 ml) was added 39.5 (0.069 mg, 0.231 mmol, 1.0 equivalent). The reaction mixture was purged with hydrogen at ambient temperature for 2 hours. After completing the reaction, the mixture was filtered through Celite and washed with methanol. The filtrate was evaporated under reduced pressure to obtain crude material, which was purified by column chromatography to obtain pure 9.5 (0.059 g, 95.06%). MS (ES): m/z 268.32 [M+H] ⁺ .

Synthesis of compound 39.7. To a solution of 1.1 (0.100 g, 0.234 mmol, 1.0 equivalent) in n-butanol (1 mL) was added compound 39.6 (0.059 g, 0.234 mmol, 1.0 equivalent) and DIPEA (0.075 g, 0.58 mmol, 2.5 equivalent). The reaction was stirred at 80°C for 3 hours. After completing the reaction, the mixture was poured into water. The product was extracted with EtOAc. The organic layers were combined, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain pure 221.6 (0.130 g, 84.58%). MS (ES): m/z 663.68 [M+H] ⁺ .

Synthesis of compound I-39. Compound 39.7 (0.130 g, 0.195 mmol, 1.0 equivalent) was dissolved in HBr/HOAc (2 mL) and stirred at room temperature for 1 hour. After completing the reaction, the mixture was poured into water, and _{basified with saturated NaHCO 3} and extracted with EtOAc. The organic layers were combined, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain a crude material, which was purified by column and preparative HPLC to obtain I-39 (0.060 g, 59.65%). MS(ES): m/z 513.50[M+H] ⁺ , ¹ H NMR (DMSO-d ₆ ,400MHz): δ 9.05(s,1H),8.91(s,1H),7.71-7.69(d,2H ), 7.63-7.59 (m, 1H), 7.30-7.25 (m, 4H), 7.13-7.11 (m, 1H), 7.05-7.03 (m, 1H), 6.99-6.95 (m, 2H), 4.46 (s , 2H) 1.77 (s, 3H).

Example 40. Synthesis of (S)-2-(4-((2-(2,6-difluorophenyl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4- d]Pyrimidine-4-yl)amino)phenyl)-2,4-dimethyl-2H-benzo[b][1,4]oxazine-3(4H)-one, I-40

Compound I-40 was prepared by isolating compound I-39 . MS(ES): m/z 513.50[M+H] ⁺ , ¹ H NMR (DMSO-d ₆ , 400MHz): δ 9.05(s, 1H), 8.90(s, 1H), 7.71-7.69(d, 2H) ), 7.63-7.59 (m, 1H), 7.30-7.25 (m, 4H), 7.13-7.11 (m, 1H), 7.05-7.03 (m, 1H), 6.99-6.95 (m, 2H), 4.45 (s , 2H) 1.77 (s, 3H).

Example 41. Synthesis of (R)-2-(4-((2-(2,6-difluorophenyl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4- d]Pyrimidine-4-yl)amino)phenyl)-2,4-dimethyl-2H-benzo[b][1,4]oxazine-3(4H)-one, I-41

Compound I-39 by chiral separation performed to obtain compound I-41. MS(ES): m/z 513.50[M+H] ⁺ , ¹ H NMR (DMSO-d ₆ ,400MHz): 9.05(s,1H),8.90(s,1H),7.71-7.69(d,2H) , 7.62-7.59 (m, 1H), 7.30-7.25 (m, 4H), 7.13-7.03 (m, 2H), 6.99-6.95 (m, 2H), 4.46 (s, 2H) 1.77 (s, 3H).

Example 42. Synthesis of 2-(2,6-difluorophenyl)-4-((4-(1,1,1-trifluoro-2-hydroxyprop-2-yl)phenyl)amino)-6 ,7-Dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, I-42

Synthesis of compound 42.1. To a solution of 4.4 (0.150g, 0.348mmol, 1.0 equivalent) in 1,4-dioxane (8mL) was added 33.3 (0.071g, 0.348mmol, 1.0 equivalent) and K ₂ CO ₃ (0.144g, 1.04mmol, 3 equivalents). The reaction mixture was degassed with argon for 10 minutes, then Pd ₂ (dba) ₃ (0.031 g, 0.034 mmol, 0.1 equivalent) and Xantphos (0.040 g, 0.069 mmol, 0.2 equivalent) were added, and degassed again for 5 minutes. The reaction was stirred at 90°C for 3 hours. After completing the reaction, the mixture was poured into water, and the product was extracted with EtOAc. The organic layers were combined, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain 42.1 (0.120 g, 57.5%). MS (ES): m/z 599.46 [M+H] ⁺ .

Synthesis of compound I-42. A solution of 42.1 (0.120 g, 0.200 mmol, 1.0 equivalent) in HBr/HOAc (3 mL) was stirred at ambient temperature for 1 hour. After the reaction was completed, the pH was adjusted to 7 _{by adding NaHCO 3 solution.} The product was extracted with EtOAc. The combined organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain I-42 (0.065 g, 72.3%). MS (ES): m/z 449.38 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ , 400MHz): δ 9.07 (s, 1H), 8.75 (s, 1H), 7.61-7.59 (d, 2H), 7.57-7.49 (m, 1H), 7.40-7.38 (d , 2H), 7.23-7.18 (m, 2H), 7.11 (s, 1H), 6.59 (s, 1H), 4.40 (s, 2H), 1.68 (s, 3H).

Example 43. Synthesis of (S)-2-(2,6-difluorophenyl)-4-((4-(1,1,1-trifluoro-2-hydroxyprop-2-yl)phenyl)amine Yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, I-43

Compound I-43 was prepared by isolating I-42 by hand. MS(ES): m/z 449.38[M+H] ⁺ , ¹ H NMR (400MHz, DMSO-d ₆ ): δ 9.15 (s, 1H), 8.78 (s, 1H), 7.62-7.60 (d, 2H) ), 7.56-7.51(m, 1H), 7.41-7.39(d, 2H), 7.24-7.20(m, 2H), 7.12(s, 1H), 6.60(s, 1H), 4.24(s, 2H), 1.68(s, 3H).

Example 44. Synthesis of (R)-2-(2,6-difluorophenyl)-4-((4-(1,1,1-trifluoro-2-hydroxy-prop-2-yl)phenyl) Amino)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, I-44

Compound I-44 was prepared by isolating I-42 by hand. MS(ES): m/z 449.38[M+H] ⁺ , ¹ H NMR (400MHz, DMSO-d ₆ ): δ 9.15 (s, 1H), 8.77 (s, 1H), 7.62-7.59 (d, 2H) ), 7.56-7.51(m, 1H), 7.41-7.38(d, 2H), 7.24-7.19(m, 2H), 7.12(s, 1H), 6.59(s, 1H), 4.42(s, 2H), 1.68(s, 3H).

Example 45. Synthesis of (S)-2-amino-2-(4-((2-(2,6-difluorophenyl)-5-oxo-6,7-dihydro-5H-pyrrolo [3,4-d]pyrimidin-4-yl)amino)phenyl)propionate hydrochloride, I-45

Synthesis of compound 45.2. Under nitrogen, to a solution of 45.1 (0.500 g, 1.23 mmol, 1.0 equivalent) in MeOH (10 mL) was added 10% Pd/C (0.2 g). _{It is purged with H 2} gas at ambient temperature for 24 hours. The reaction mixture was filtered through Celite, washed with methanol, and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain 232.1 (0.26g, 71.2%) MS(ES): m/z 294.35[ M+H] ⁺ .

Synthesis of compound 45.3. Compound 45.2 was prepared by isolating 232.1 (0.085g), MS(ES): m/z 294.35[M+H] ⁺ , ¹ H NMR (400MHz, DMSO-d ₆ ): δ 7.07-7.04( d, 2H), 6.50-6.48 (d, 2H), 5.10 (s, 2H), 3.55 (s, 3H), 1.67 (s, 3H), 1.36 (s, 9H).

Synthesis of compound 45.4. To a solution of 1.1 (0.120g, 0.278mmol, 1.0 equivalent) in n-butanol (5ml) was added 45.3 (0.081g, 0.278mmol, 1.0 equivalent) and DIPEA (0.107g, 0.835mmol, 3.0 equivalent). The reaction was stirred at 100°C for 2 hours. After the reaction was completed, the solvent was removed under reduced pressure to obtain a crude material of 45.4 (0.120 g, 62.61%). MS (ES): m/z 689.72 [M+H] ⁺ .

Synthesis of compound 45.5. Compound 45.4 (0.120 g, 0.173 mmol, 1.0 equivalent) was dissolved in HBr/HOAc (2 mL) and stirred at room temperature for 1 hour. After completing the reaction, the mixture was poured into water, and _{basified with saturated NaHCO 3} solution and extracted with EtOAc. The organic layers were combined, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain a pure 45.5 (0.055 g, 71.9%). MS (ES): m/z 439.42 [M+H] ⁺ .

Synthesis of compound I-45. Compound 45.5 (0.055 g, 0.125 mmol, 1.0 equivalent) was dissolved in MeOH (2 mL) at 0°C. 2N NaOH solution (0.165ml, 0.375mmol, 3.0 equivalents) was added at the same temperature. The reaction mixture was stirred at room temperature for 1 hour. After completing the reaction, the mixture was acidified by using a solution of HCl in dioxane. The solvent was removed under reduced pressure to obtain a crude material, which was purified by preparative HPLC to obtain I-45 (0.025 g, 46.9%). MS(ES): m/z 425.40[M+H] ⁺ ; ¹ H NMR (400MHz, MeOD): δ 8.18 (s, 1H), 7.89-7.86 (d, 2H), 7.60-7.54 (m, 3H) , 7.17-7.11 (m, 2H), 4.51 (s, 2H), 1.89 (s, H).

Example 46. Synthesis of (R)-2-amino-2-(4-((2-(2,6-difluorophenyl)-5-oxo-6,7-dihydro-5H-pyrrolo [3,4-d]pyrimidin-4-yl)amino)phenyl)propionate hydrochloride, I-46

Synthesis of compound 46.1. The compound 46.1 was prepared by the parallel separation of 45.2 . MS(ES): m/z 294.35[M+H] ⁺ , ¹ H NMR (400MHz, DMSO-d ₆ ): δ 7.06-7.04(d,2H), 6.50-6.48(d,2H), 5.10(s , 2H), 3.55 (s, 3H), 1.67 (s, 3H), 1.36 (s, 9H).

Synthesis of compound 46.2. Compound 46.2 was prepared using equivalent procedures as described for the synthesis of compound 45.4 . MS (ES): m/z 689.72 [M+H] ⁺ .

Synthesis of compound 46.3. Compound 46.3 was prepared using the same procedure as described for the preparation of compound 45.5 . MS (ES): m/z 439.42 [M+H] ⁺ .

Synthesis of compound I-46. Using the same procedure as described for the preparation of compounds I-45 Preparation of Compound I-46. MS(ES): m/z 425.40[M+H] ⁺ , ¹ H NMR (400MHz, MeOD): δ 8.30 (s, 1H), 7.88-7.86 (d, 2H), 7.58-7.52 (m, 3H) ,7.16-7.12(m,2H),4.51(s,2H),1.89(s,3H).

Example 47. Synthesis of 4-((5-(7-oxa-4-azaspiro[2.5]oct-4-yl)pyridin-2-yl)amino)-2-(2,6-difluorobenzene Yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, 1-47

Synthesis of compound 47.1. To a solution of 20.1 (0.120g, 0.591mmol, 1.0 equivalent) in 1,4-dioxane (3ml) was added 7-oxa-4-azaspiro[2.5]octane (0.088g, 0.591mmol, 1.0 Equivalent) and sodium tert-butoxide (0.17 g, 1.77 mmol, 3.0 equivalent). The reaction mixture was degassed under an argon atmosphere for 10 minutes, and then Pd ₂ (dba) ₃ (0.054 g, 0.059 mmol, 0.1 equivalent) and 2-dicyclohexylphosphino-2'-(N,N-dimethyl) were added Amino)-biphenyl (0.046 g, 0.118 mmol, 0.2 equivalents), and degas again for 5 minutes. The reaction was stirred at 100°C for 3 hours. After completing the reaction, the mixture was poured into water, and the product was extracted with EtOAc. The organic layers were combined, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain 47.1 (0.059 g, 42.43%). MS (ES): m/z 235.24 [M+H] ⁺ .

Synthesis of compound 47.2. Under a nitrogen atmosphere, to a solution of 47.1 (0.059 g, 0.25 mmol, 1.0 equivalent) in MeOH (8 mL) was added 10% Pd/C (0.06 g). Purged with H ₂ gas for 1 hour. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain a crude material 47.2 (0.045g, 87.41%), which was used as is in the next step, MS(ES): m/z 205.26[M+ H] ⁺ .

Synthesis of compound 47.3. To a solution of 4.4 (0.100g, 0.232mmol, 1.0 equivalent) in 1,4-dioxane (3ml) was added 47.2 (0.045g, 0.232mmol, 1.0 equivalent) and K ₂ CO ₃ (0.080g, 0.581mmol, 2.5 equivalents). The reaction mixture was degassed for 10 minutes under an argon atmosphere, then Pd ₂ (dba) ₃ (0.021 g, 0.023 mmol, 0.1 equivalent) and Xantphos (0.026 g, 0.046 mmol, 0.2 equivalent) were added, and degassed again for 5 minutes , The reaction was stirred at 100°C for 3 hours. After completing the reaction, the mixture was poured into water, and the product was extracted with EtOAc. The organic layers were combined, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain 47.3 (0.075 g, 53.89%). MS (ES): m/z 599.64 [M+H] ⁺ .

Synthesis of compound I-47. Compound 47.3 (0.075 g, 0.125 mmol, 1.0 equivalent) was dissolved in TFA (5 mL) and heated at 70°C for 6 hours. After completing the reaction, the trifluoroacetic acid was removed under reduced pressure. Water was added to the reaction mixture, _{basified with saturated NaHCO 3} and extracted with EtOAc. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain I-47 (0.032 g, 56.9%). MS(ES): m/z 449.46[M+H] ⁺ , ¹ H NMR (DMSO-d ₆ , 400MHz): δ 9.53(s, 1H), 8.82(s, 1H), 8.40(s, 1H), 8.12 (s, 1H), 7.59-7.47 (m, 2H), 7.28-7.24 (t, 2H), 7.10-7.08 (d, 1H), 4.41 (s, 2H), 3.63-3.53 (m, 2H), 3.50-3.40 (m, 4H), 0.90-0.84 (t, 2H), 0.72 (s, 2H).

Example 48. Synthesis of 2-(2,6-difluorophenyl)-4-((4-(1,3-dimethyl-2-oxoindolin-3-yl)phenyl)amino )-6,7-Dihydro-5H-pyrrolo[3,4-d]pyrimidin-5-one, I-298

Synthesis of compound 48.2. To a solution of compound 48.1 (5 g, 20.57 mmol, 1.0 equivalent) in THF (50 mL) was added MeI (3.21 g, 22.6 mmol, 1.1 equivalent) and 18-crown-6 (1.35 g, 5.14 mmol, 0.25 equivalent). The reaction was cooled to -78°C. Potassium tert-butoxide (2.53 g, 22.63 mmol, 1.1 equivalents) was added to the reaction mixture, and stirred at room temperature for 4 days. After completing the reaction, the mixture was poured into water, NH ₄ Cl solution was added and the product was extracted with EtOAc. The organic layers were combined, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain pure 48.2 (5 g, 89.09%). MS (ES): m/z 257.13 [M+H] ⁺ .

Synthesis of compound 48.3. To a solution of compound 48.2 (5.0 g, 19.45 mmol, 1.0 equivalent) in EtOH (100 mL) was added a solution of NaOH (3.9 g, 97.2 mmol, 5.0 equivalent) in water (20 mL). The reaction was stirred at room temperature for 3 hours. After completing the reaction, the solvent was evaporated under reduced pressure, and the reaction mixture was poured into water. The aqueous layer was acidified with HCl, and the product was extracted with EtOAc. The organic layers were combined, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain pure 48.3 (3.73 g, 83.7%). MS (ES): m/z 229.07 [M+H] ⁺ .

Synthesis of compound 48.4. At room temperature, to a solution of 48.3 (3.7 g, 16.3 mmol, 1.0 equivalent) in CH ₂ Cl ₂ (60 ml) was added 2-fluoro-N-methylaniline (2.03 g, 16.28 mmol, 1.0 equivalent). The reaction mixture was cooled to 0°C and DMAP (0.397 g, 3.25 mmol, 0.2 equivalent) was added. At 0°C, additional dicyclohexylcarbodiimide (4.0 g, 19.5 mmol, 1.2 equivalents) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 24 hours. After completing the reaction, the mixture was poured into water and extracted with CH ₂ Cl ₂ . The organic layers were combined, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain pure 48.4 (4 g, 73.1%). MS (ES): m/z 336.20 [M+H] ⁺ .

Synthesis of compound 48.5. To a solution of compound 48.4 (1 g, 2.97 mmol, 1.0 equivalent) in DMF (10 mL) was added potassium tert-butoxide (0.66 g, 5.95 mmol, 2.0 equivalent). The reaction mixture was stirred at 80°C for 24 hours. After completing the reaction, the mixture was poured into water, and the product was extracted with EtOAc. The organic layers were combined, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain 48.5 (0.28 g, 29.8%). MS (ES): m/z 316.20 [M+H] ⁺ .

Synthesis of compound 48.6. To a solution of 48.5 (0.28g, 0.88mmol, 1.0 equivalent) in 1,4-dioxane (20mL) was added benzylamine (0.19g, 1.77mmol, 2.0 equivalent) and Cs ₂ CO ₃ (0.86g, 2.65mmol) , 3.0 equivalents). Degas the reaction mixture with argon for 30 minutes, then add Pd ₂ (dba) ₃ (0.081g, 0.09mmol, 0.1 equivalent) and 2-dicyclohexylphosphino-2'-(N,N-dimethylamine) Yl)-biphenyl (0.069 g, 0.18 mmol, 0.2 equivalents), and degas the suspension again for 5 minutes. The reaction was stirred at 100°C for 3 hours. After completing the reaction, the mixture was poured into water, and the product was extracted with EtOAc. The organic layers were combined, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain 48.6 (0.15 g, 49.46%). MS (ES): m/z 342.44 [M+H] ⁺ .

Synthesis of compound 48.7. Under nitrogen, to a _{suspension of Pd(OH) 2} (0.02 g) in MeOH (5 ml) was added 48.6 (0.15 g, 0.44 mmol, 1.0 equivalent). It was _{purged with H 2} gas for 1 hour. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain a crude material of 48.7 (0.1 g, 90.5%), which was used as is in the next step, MS (ES): m/z 252.32 [M+ H] ⁺ .

Synthesis of compound 48.8. To a solution of 1.1 (0.08 g, 0.185 mmol, 1.0 equivalent) in n-butanol (2 mL) was added 48.7 (0.046 g, 0.185 mmol, 1.0 equivalent) and DIPEA (0.071 g, 0.556 mmol, 3.0 equivalent). The reaction mixture was stirred at 90°C for 3 hours. After completing the reaction, the mixture was poured into water, and the product was extracted with EtOAc. The organic layers were combined, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain 48.8 (0.08 g, 66.7%). MS (ES): m/z 647.68 [M+H] ⁺ .

Synthesis of compound I-48. Compound 48.8 (0.08 g, 0.123 mmol, 1.0 equivalent) was dissolved in HBr/HOAc (1 ml). The reaction was stirred at room temperature for 30 minutes. After the reaction was completed, water was added to the reaction mixture, and _{basified with saturated NaHCO 3} and extracted with EtOAc. The organic layers were combined, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain I-48 (0.05 g, 81.4%). MS(ES): m/z 497.51[M+H] ⁺ ; ¹ H NMR (DMSO-d ₆ , 400MHz): δ 9.06 (s, 1H), 8.90 (s, 1H), 7.71-7.04 (m, 11H) ), 4.47 (s, 2H), 3.18 (s, 3H) 1.66 (s, 3H).

Example 49. Synthesis of 2-(2,6-difluorophenyl)-4-((2-isopropyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl )Amino)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, I-49

Synthesis of compound 49.2. Compound 49.1 (19 g, 107.9 mmol, 1.0 equivalent) was dissolved in CH ₂ Cl ₂ (200 mL) and cooled at 0°C. N,N-diisopropylamine (53.5 ml, 0.375 mmol, 3.48 equivalents) was added and the mixture was stirred at room temperature for 15 hours. After completing the reaction, the reaction mixture was poured into water, and the product was extracted _{with CH 2} Cl _2. The organic layers were combined, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain 49.2 (24 g, 92.35%). MS (ES): m/z 240.73 [M+H] ⁺ .

Synthesis of compound 49.3. Compound 49.2 (24.0g, 100mmol, 1.0 equivalent) was dissolved in ether (200mL) and cooled to -75°C. At -78°C, N,N-diisopropylamine (72ml, 500mmol) was added dropwise to the reaction mixture , 5 equivalents) and n-BuLi (200ml, 500mmol, 5.0 equivalents). The reaction was stirred at -78°C for 15 minutes, and then DMF (12 ml, 150 mmol, 1.5 equivalents) was added at -78°C and the reaction was stirred for 1 hour. After completing the reaction, the mixture was poured into water, quenched with 10% citric acid, and extracted with ether. The organic layers were combined, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain 49.3 (23.3 g, 86.8%). MS (ES): m/z 268.74 [M+H] ⁺ .

Synthesis of compound 49.4. To a solution of 49.3 (23.25 g, 86.51 mmol, 1.0 equivalent) in ethanol (500 ml) was added NaBH ₄ (23.34 g, 614 mmol, 7.1 equivalent). The reaction was stirred at room temperature for 2 hours. After completing the reaction, the reaction mixture was poured into water, quenched with 1N HCl, and extracted with EtOAc. The organic layers were combined, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain 49.4 (20 g, 85.4%). MS (ES): m/z 270.76 [M+H] ⁺ .

Synthesis of compound 49.5. Compound 49.4 (20 g, 74.1 mmol, 1.0 equivalent) was added to the 6N HCl solution. The reaction was heated at 120°C for 2 hours. After completing the reaction, the mixture was cooled, basified with sodium carbonate, and the product was extracted with EtOAc. The organic layers were combined, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain 49.5 (5.69 g, 45.43%). MS (ES): m/z 169.56 [M+H] ⁺ .

Synthesis of compound 49.6. To a solution of 49.5 (5.69 g, 33.55 mmol, 1.0 equivalent) in ethanol (100 ml) was added NaBH ₄ (8.92 g, 234.9 mmol, 7.0 equivalent). The reaction was stirred at room temperature for 2 hours. After completing the reaction, the mixture was poured into water, quenched with 1N HCl solution, and extracted with EtOAc. The organic layers were combined, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain 49.6 (2.1 g, 36.05%). MS (ES): m/z 173.60 [M+H] ⁺ .

Synthesis of compound 49.7. To a solution of 49.6 (2.1 g, 12.1 mmol, 1.0 equivalent) in CH ₂ Cl ₂ (30 mL) was added SOCl ₂ (7.22 g, 60.7 mmol, 5.0 equivalent). The reaction was heated at 50°C until it became clear. Thionyl chloride is removed by distillation. Anhydrous CH ₂ Cl _{2 was added} , and the reaction mixture was cooled to 0°C. Isopropylamine (3.58 g, 60.7 mmol, 5.0 equivalents) was added under a nitrogen atmosphere, and the reaction mixture was stirred at the same temperature for 1.5 hours. After completing the reaction, the mixture was poured into water, and the product was extracted _{with CH 2} Cl _2. The organic layers were combined, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain 49.7 (0.6 g, 25.22%). MS (ES): m/z 196.68 [M+H] ⁺ .

Synthesis of compound 49.8. Compound 49.7 (0.55 g, 28.06 mmol, 1.0 equivalent) was dissolved in 1,4-dioxane (20 ml) and degassed with argon for 10 minutes. To the reaction mixture were added 2,4-dimethoxybenzylamine (0.703 g, 42.09 mmol, 1.5 equivalents) and cesium carbonate (1.828 g, 5.612 mmol, 2.0 equivalents). The reaction mixture was degassed for another 10 minutes. To the reaction mixture was added dicyclohexylphosphino-2'-(N,N-dimethylamino)-biphenyl (0.220g, 0.561mmol, 0.5 equivalent) and Pd ₂ (dba) ₃ (0.256g, 0.280mmol , 0.1 equivalent) and heated at 110°C for 24 hours. After completing the reaction, the mixture was poured into water and extracted with CH ₂ Cl ₂ . The organic layers were combined, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain pure 49.8 (0.35 g, 71.0%). MS (ES): m/z 176.24 [M+H] ⁺ .

Synthesis of compound 49.9. Compound 49.8 (0.25 g, 0.764 mmol, 1.0 equivalent) was dissolved in CH ₂ Cl ₂ (5 mL). To the reaction mixture was added triethylsilane (0.27 g, 2.29 mmol, 3.0 equivalents) and TFA (3 mL). The reaction mixture was stirred at room temperature for 24 hours. After completing the reaction, the mixture was concentrated under reduced pressure, _{basified by NaHCO 3} solution, and extracted with EtOAc. The organic layers were combined, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain a crude material, which was purified by column to obtain 49.9 (0.075 g, 29.8%). MS (ES): m/z 177.25 [M+H] ⁺ .

Synthesis of compound 49.10. To a solution of 4.4 (0.150g, 0.348mmol, 1.0 equivalent) in 1,4-dioxane (3ml) was added 49.9 (0.067g, 0.383mmol, 1.1 equivalent) and K ₂ CO ₃ (0.120g, 0.871mmol, 2.5 equivalents). The reaction mixture was degassed with argon for 10 minutes, then Pd ₂ (dba) ₃ (0.031 g, 0.034 mmol, 0.1 equivalent) and Xantphos (0.040 g, 0.069 mmol, 0.2 equivalent) were added, and the suspension was degassed again 5 minute. The reaction was stirred at 110°C for 1.5 hours. After completing the reaction, the mixture was poured into water, and the product was extracted with EtOAc. The organic layers were combined, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain 49.10 (0.035 g, 17.6%). MS (ES): m/z 571.63 [M+H] ⁺ .

Synthesis of compound I-49. Compound 49.10 (0.030 g, 0.052 mmol, 1.0 equivalent) was dissolved in HBr/HOAc (0.5 ml), and the reaction was stirred at room temperature for 1 hour. After the reaction was completed, water was added. The mixture was basified with saturated bicarbonate solution, and the product was extracted with EtOAc. The organic layers were combined, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain a dehydrated crude material, which was purified by column chromatography to obtain I-49 (0.002 g, 9.0%). MS(ES): m/z 421.45[M+H] ⁺ ; ¹ H NMR (CD ₃ OD, 400MHz): δ 8.70 (s, 1H), 8.24 (s, 1H), 7.56-7.52 (m, 1H) ,7.17-7.13(t,2H),7.05(s,1H),4.48(s,2H),4.04-4.01(s,4H),2.88-2.85(m,1H),1.25-1.23(d,3H) .

Example 50. Synthesis of 4-((4-(4-oxa-7-azaspiro[2.5]octane-7-carbonyl)phenyl)amino)-2-(2,6-difluorophenyl) -6,7-Dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, I-50

Synthesis of compound 50.1. At 0°C, to a solution of p-aminobenzoic acid (0.080 g, 0.583 mmol, 1.0 equivalent) in DMF (2 mL) was added HATU (0.33 g, 0.88 mmol, 1.5 equivalent). The reaction was stirred at 0°C for 45 minutes. The reaction was warmed to ambient temperature and stirred for another ten minutes. Add another portion of 4-oxa-7-azaspiro[2.5]octane (0.104g, 0.700mmol, 1.2 equivalents) and DIPEA (0.150g, 1.17mmol, 2.0 equivalents) at 0°C, and at room temperature The reaction was stirred for 2 hours. After completing the reaction, the mixture was poured into water, and the product was extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain crude material. The crude material was purified by column chromatography to provide 50.1 (0.070 g, 51.66%). MS (ES): m/z 232.28 [M+H] ⁺ .

Synthesis of compound 50.2. To a solution of 4.4 (0.100g, 0.232mmol, 1.0 equivalent) in 1,4-dioxane (3mL) was added 50.1 (0.054g, 0.23mmol, 1.0 equivalent) and K ₂ CO ₃ (0.064g, 0.47mmol, 2.0 equivalent). The reaction mixture was degassed for 10 minutes under an argon atmosphere, then Pd ₂ (dba) ₃ (0.021 g, 0.023 mmol, 0.1 equivalent) and Xantphos (0.026 g, 0.046 mmol, 0.2 equivalent) were added, and degassed again for 5 minutes . The reaction was stirred at 100°C for 2 hours. After completing the reaction, the reaction mixture was poured into water, and the product was extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain 50.2 (0.098, 67.4%). MS (ES): m/z 626.66 [M+H] ⁺ .

Synthesis of compound I-50. Compound 50.2 (0.098 g, 0.156 mmol, 1.0 equivalent) was dissolved in HBr/HOAc (33% solution, 3 mL), and stirred at room temperature for 1 hour. After completing the reaction, the mixture was poured into ice water, and _{basified with saturated NaHCO 3} and extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain I-50 (0.041 g, 55.0%). MS(ES): m/z 476.48[M+H] ⁺ ; ¹ H NMR (DMSO-d ₆ ,400MHz): 9.17(s,1H),8.77(s,1H),7.56-7.50(m,1H) , 7.43 (s, 4H), 7.24-7.20 (m, 3H), 4.40 (s, 2H), 3.64-3.43 (m, 6H), 0.85-0.52 (m, 4H).

Example 51. Synthesis of 4-((4-(7-oxa-4-azaspiro[2.5]octane-4-carbonyl)phenyl)amino)-2-(2,6-difluorophenyl) -6,7-Dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, I-51

Synthesis of compound 51.1. At 0°C, to a solution of 7-oxa-4-azaspiro[2.5]octane (0.080 g, 0.540 mmol, 1.0 equivalent) in anhydrous THF was added K ₂ CO ₃ (0.149 g, 1.081 mmol, 2.0 Equivalent) and p-nitrobenzyl chloride (0.1 g, 0.54 mmol, 1.0 equivalent). The reaction mixture was stirred at room temperature for 2 hours. After completing the reaction, the mixture was poured into crushed ice, and neutralized with saturated NaHCO ₃ and extracted with EtOAc. The organic layers were combined, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain 51.1 (0.12 g, 84.9%). MS (ES): m/z 262.27 [M+H] ⁺ .

Synthesis of compound 51.2. To a suspension of Pd/C (0.025 g) in methanol (3 mL) was added 51.1 (0.12 g, 0.46 mmol, 1.0 equivalent) in MeOH (2 mL). The suspension was purged with H ₂ gas for 1.5 hours. After completing the reaction, the mixture was filtered through Celite, washed with methanol, and the filtrate was concentrated under reduced pressure to obtain a crude material. The crude material was purified by column chromatography to obtain pure 51.2 (0.06g, 56.5%). MS (ES): m/z 232.28 [M+H] ⁺ .

Synthesis of compound 51.3. To a mixture of 4.4 (0.10g, 0.23mmol, 1.0 equivalent) in 1,4-dioxane (3mL) was added 51.2 (0.053g, 0.232mmol, 1.0 equivalent) and K ₂ CO ₃ (0.064g, 0.47mmol, 2.0 equivalent). The reaction mixture was degassed for 10 minutes under an argon atmosphere, and then Pd ₂ (dba) ₃ (0.021 g, 0.023 mmol, 0.1 equivalent) and Xantphos (0.026 g, 0.046 mmol, 0.2 equivalent) were added, and degassed again for 5 minutes. The reaction was stirred at 100°C for 12 hours. After completing the reaction, the mixture was poured into water, and the product was extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain 51.3 (0.093 g, 63.94%). MS (ES): m/z 626.66 [M+H] ⁺ .

Synthesis of compound I-51. Compound 51.3 (0.093 g, 0.148 mmol, 1.0 equivalent) was dissolved in HBr/HOAc (2 mL), and the reaction was stirred at room temperature for 1 hour. After completing the reaction, the reaction mixture was poured into water, _{basified with saturated NaHCO 3} and extracted with EtOAc. The organic layers were combined, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain I-51 (0.041 g, 57.9%). MS(ES): m/z 476.48[M+H] ⁺ ; ¹ H NMR (DMSO-d ₆ , 400MHz): 9.17 (s, 1H), 8.78 (s, 1H), 7.56-7.39 (m, 5H) , 7.24-7.20 (m, 3H), 4.41 (s, 2H), 3.63 (s, 4H), 3.54 (s, 2H), 0.78 (s, 4H).

Example 52. Synthesis of 4-((5-(2-oxa-8-azaspiro[4.5]dec-8-yl)pyridin-2-yl)amino)-2-(2,6-difluorobenzene Yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, I-52

Synthesis 52.3. To a mixture of 52.1 (0.045g, 0.118mmol, 1.0 equivalent) in 1,4-dioxane (1.0mL) was added 52.2 (0.023g, 0.118mmol, 1.0 equivalent) and K ₂ CO ₃ (0.048g, 0.354mmol) , 3.0 equivalents). Degas the reaction mixture with argon for 10 minutes, then add Pd ₂ (dba) ₃ (0.010 g, 0.011 mmol, 0.1 equivalent) and Xantphos (0.013 g, 0.023 mmol, 0.2 equivalent), and degas the mixture for another 5 minutes . The reaction was stirred at 100°C for 1 hour. After completing the reaction, the mixture was poured into water, and the product was extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain crude material. The crude material was purified by column chromatography to provide 52.3 (0.045 g, 61.8%). MS (ES): m/z 577.63 [M+H] ⁺ .

Synthesis of I-52. Compound 52.3 (0.045 g, 0.077 mmol, 1.0 equivalent) was dissolved in CH ₂ Cl ₂ (1 mL), and TFA (0.5 mL) was added to the reaction. The reaction was stirred at room temperature for 1 hour. After completing the reaction, the mixture was poured into water, _{basified with NaHCO 3} solution, and extracted with CH ₂ Cl ₂ . The organic layers were combined, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain I-52 (0.025 g, 59.9%). MS(ES): m/z 477.52[M+H] ⁺ ; ¹ H NMR (DMSO-d ₆ , 400MHz): δ 9.50(s, 1H), 8.80(s, 1H), 8.36(s, 1H), 8.03(d,1H), 7.60-7.53(m,1H), 7.47-7.44(dd,1H), 7.27-7.23(t,2H), 7.09-7.07(d,1H), 4.40(s,2H), 3.76-3.73 (t, 2H), 3.46 (s, 2H), 3.19-3.07 (m, 4H), 1.74-1.70 (t, 2H), 1.61-1.53 (m, 4H).

Example 53. Synthesis of 4-((5-(1-oxa-9-azaspiro[5.5]undec-9-yl)pyridin-2-yl)amino)-2-(2,6-di (Fluorophenyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, I-53

Synthesis of compound 53.2. To a solution of 53.1 (0.17g, 1.19mmol, 1.0 equivalent) in DMSO (3mL) was added 1-oxa-9-azaspiro[5.5]undecane (0.229g, 0.119mmol, 1.0 equivalent) and DIPEA ( 1.54g, 11.9mmol, 10.0 equivalent). The reaction was stirred at 110°C for 2 hours. After completing the reaction, the mixture was poured into water and extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain crude material. The crude material was purified by trituration with hexane to provide 53.2 (0.2 g, 60.3%). MS (ES): m/z 277.32 [M+H] ⁺ .

Synthesis of compound 53.3. Under a nitrogen atmosphere, to a suspension of 10% Pd/C (0.05 g) in MeOH (2 mL) was added a solution of 53.2 (0.2 g, 0.72 mmol, 1.0 equivalent) in MeOH (3.0 mL). The reaction mixture was purged with H ₂ gas for 2 hours. After completing the reaction, the mixture was filtered through Celite, washed with MeOH, and concentrated under reduced pressure. The crude material was purified by column chromatography to provide 53.3 (0.14 g, 78.5%). MS (ES): m/z 247.34 [M+H] ⁺ .

Synthesis of compound 53.4. To a mixture of 4.4 (0.1g, 0.23mmol, 1.0 equivalent) in 1,4-dioxane (3mL) was added 53.3 (0.063g, 0.255mmol, 1.1 equivalent) and K ₂ CO ₃ (0.064g, 0.465mmol, 2.0 equivalent). The reaction mixture was degassed with argon gas for 10 minutes, then Pd ₂ (dba) ₃ (0.021 g, 0.023 mmol, 0.1 equivalent) and Xantphos (0.026 g, 0.046 mmol, 0.2 equivalent) were added, and the suspension was degassed again 5 minutes. The reaction was stirred at 110°C for 1 hour. After completing the reaction, the mixture was poured into water and extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain crude material. The crude material was purified by column chromatography to provide 53.4 (0.09g, 60.4%). MS (ES): m/z 641.72 [M+H] ⁺ .

Synthesis of compound I-53. Compound 53.4 (0.09 g, 0.14 mmol, 1.0 equivalent) was dissolved in HBr/HOAc (3 mL), and the reaction was stirred at room temperature for 1 hour. After completing the reaction, the mixture was poured into water, _{basified with NaHCO 3} solution, and extracted with EtOAc. The organic layers were combined, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain a crude material. The crude material was purified by column chromatography to provide I-53 (0.038g, 55.1%). MS(ES): m/z 491.54[M+H] ⁺ ; ¹ H NMR (DMSO-d ₆ , 400MHz): δ 9.49(s, 1H), 8.79(s, 1H), 8.35(s, 1H), 8.02(d,2H),7.59-7.54(m,1H),7.46-7.43(dd,1H),7.27-7.23 (t,2H),7.08-7.06(d,1H),4.40(s,2H), 3.58-3.55 (t, 2H), 3.33-3.28 (t, 2H), 2.98-2.93 (t, 2H), 1.89-1.86 (d, 2H), 1.59-1.39 (m, 8H).

Example 54. Synthesis of 4-((4-(1-oxa-9-azaspiro[5.5]undecane-9-carbonyl)phenyl)amino)-2-(2,6-difluorophenyl )-6,7-Dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, I-54

Synthesis of compound 54.2. To a solution of 54.1 (0.2g, 1.08mmol, 1.0 equivalent) in CH ₂ Cl ₂ (2mL) was added 1-oxa-9-azaspiro[5.5]undecane (0.21g, 1.08mmol, 1.0 equivalent) And DIPEA (0.33 g, 3.24 mmol, 3.0 equivalents). The reaction was stirred at room temperature for 1 hour. After completing the reaction, the mixture was poured into water and extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain pure 54.2 (0.16 g, 48.8%). MS (ES): m/z 304.35 [M+H] ⁺ .

Synthesis of compound 54.3. Under nitrogen, to a suspension of 10% Pd/C (0.05 g) in MeOH (2 mL) was added a solution of 54.2 (0.16 g, 0.53 mmol, 1.0 equivalent) in MeOH (3 mL). The reaction mixture was purged with H ₂ gas for 1 hour. After completing the reaction, the mixture was filtered through Celite and washed with MeOH. The resulting filtrate was concentrated under reduced pressure to provide 54.3 (0.05 g, 34.7%). MS (ES): m/z 274.36 [M+H] ⁺ .

Synthesis of compound 54.4. To a mixture of 4.4 (0.075g, 0.174mmol, 1.0 equivalent) in 1,4-dioxane (3mL) was added 54.3 (0.047g, 0.174mmol, 1.0 equivalent) and K ₂ CO ₃ (0.048g, 0.348mmol, 2.0 equivalent). The reaction mixture was degassed with argon for 10 minutes, and then Pd ₂ (dba) ₃ (0.015 g, 0.017 mmol, 0.1 equivalent) and Xantphos (0.02 g, 0.034 mmol, 0.2 equivalent) were added. Degas the suspension for another 5 minutes. The reaction was stirred at 110°C for 2 hours. After completing the reaction, the mixture was poured into water and extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain crude material. This crude material was purified by column chromatography to provide 54.4 (0.07g, 60.1%). MS (ES): m/z 668.74 [M+H] ⁺ .

Synthesis of compound I-54. Compound 54.4 (0.07 g, 0.104 mmol, 1.0 equivalent) was dissolved in HBr/HOAc (3 mL, 33% HBr in AcOH), and the reaction was stirred at room temperature for 1 hour. After completing the reaction, the mixture was poured into water, _{basified with saturated NaHCO 3} solution, and the product was extracted with EtOAc. The organic layers were combined, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain I-54 (0.029 g, 53.4%). MS(ES): m/z 518.56[M+H] ⁺ ; ¹ H NMR (DMSO-d ₆ , 400MHz): δ 9.15 (s, 1H), 8.77 (s, 1H), 7.57-7.50 (m, 1H) ),7.41(s,4H),7.23-7.18(m,3H),4.41(s,2H),4.09(m,2H),3.56(m,2H),3.16(m,2H),1.84-1.82( m, 4H), 1.56 (m, 2H), 1.43-1.40 (m, 6H).

Example 55. Synthesis of 2-(2,6-difluorophenyl)-4-((5-(1-(3,6-dihydro-2H-piperan-4-yl)-3,5,5- Trimethyl-2-oxopyrrolidin-3-yl)pyridin-2-yl)amino)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, I-55

Synthesis of compound 55.2. At room temperature, acetyl chloride (15.1 g, 192.3 mmol, 3.3 equivalents) was slowly added to MeOH (100 mL). The reaction was stirred at room temperature for 15 minutes. Compound 55.1 (10 g, 58.3 mmol, 1.0 equivalent) was slowly added, and the reaction mixture was stirred at room temperature for 16 hours. After completing the reaction, the solvent was evaporated under reduced pressure. _{Saturated NaHCO 3} solution was added to the reaction mixture, and the product was extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain pure 55.2 (10.0 g, 92.4%). MS (ES): m/z 185.61 [M+H] ⁺ .

Synthesis of compound 55.3. At room temperature, to a solution of 55.2 (10.0g, 54.0mmol, 1.0 equivalent) in toluene (100mL) was added K ₂ CO ₃ (16.5g, 118.8mmol, 2.2 equivalent), paraformaldehyde (2.66g, 70.19mmol) , 1.3 equivalents) and tetrabutylammonium chloride (1.5g, 5.4mmol, 0.1 equivalents). The reaction was stirred at room temperature for 2 hours. After completing the reaction, the reaction mixture was poured into water and extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain pure 1.2 (2.6 g, 24.42%). MS (ES): m/z 197.62 [M+H] ⁺ .

Synthesis of compound 55.4. At room temperature, to a solution containing 55.3 (2.6g, 13.2mmol, 1.0 equivalent) in CH ₃ CN (40mL) was added 2-nitropropane (1.41g, 15.8mmol, 1.2 equivalent) and DBU (2.40g, 15.82) mmol, 1.2 equivalents). The reaction was stirred at room temperature for 6 hours. After completing the reaction, CH ₃ CN was evaporated under reduced pressure, water was added to the reaction mixture, and the product was extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain crude material. The crude material was purified by column chromatography to provide 55.3 (2.2g, 58.3%). MS (ES): m/z 286.71 [M+H] ⁺ .

Synthesis of compound 55.5. At 0°C, to a solution of NaH (0.40 g, 16.9 mmol, 2.2 equivalents) in DMF (20 mL) was added 55.4 (2.2 g, 7.68 mmol, 1.0 equivalent), and the reaction was stirred at 0°C for 5 minutes. At 0°C, methyl iodide (2.73 g, 19.2 mmol, 2.5 equivalents) was added dropwise to the reaction mixture. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, water was added to the reaction mixture, and the product was extracted with EtOAc. The organic layers were combined, washed with brine solution, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain pure 55.5 (1.5 g, 65.0%). MS (ES): m/z 300.74 [M+H] ⁺ .

Synthesis of compound 55.6. To a solution of 55.5 (1.5 g, 5.0 mmol, 1.0 equivalent) in EtOH (15.0 mL) was added iron powder (2.8 g, 50.0 mmol, 10.0 equivalent) and NH ₄ Cl (2.65 g, 50.0 mmol, 10.0 equivalent). The reaction mixture was stirred at 80°C for 2 hours. After the reaction was completed, water was added to the reaction mixture, and the product was extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain a pure product. Dichloromethane was added to the pure product, and the reaction was stirred overnight at room temperature to obtain the pure cyclized product 55.6 (0.8 g, 67.2%). MS (ES): m/z 238.72 [M+H] ⁺ .

Synthesis of compound 55.7. To a solution of 55.7 (0.8g, 3.36mmol, 1.0 equivalent) in 1,4-dioxane (5.0mL) was added Cs ₂ CO ₃ (3.27g, 10.1mmol, 3.0 equivalent) and CuI (0.063g, 0.336mmol) , 0.1 equivalent). The reaction mixture was degassed with argon at room temperature for 15 minutes. Add 4-bromo-3,6-dihydro-2H-piperan (1.64g, 10.1mmol, 3.0 equivalents) and N,N -dimethylethylenediamine (0.029g, 0.34mmol, 0.1 equivalents) to the reaction mixture . The reaction was stirred in a microwave reactor at 160°C for 1 hour. After the reaction was completed, water was added to the reaction mixture, and the product was extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain 55.7 (0.3 g, 27.9%). MS (ES): m/z 320.82 [M+H] ⁺ .

Synthesis of compound 55.8. To a solution of 55.7 (0.16g, 0.5mmol, 1.0 equivalent) in 1,4-dioxane (5mL) was added 2,4-dimethoxybenzylamine (0.11g, 0.65mmol, 1.3 equivalent) and Cs ₂ CO ₃ (0.325 g, 10.0 mmol, 2.0 equivalents). The reaction mixture was degassed with argon at room temperature for 30 minutes. Devphos ligand (0.039 g, 0.1 mmol, 0.2 equivalent) and Pd ₂ (dba) ₃ (0.045 g, 0.05 mmol, 0.1 equivalent) were added to the reaction mixture. The reaction was stirred at 100°C for 3 hours. After the reaction was completed, water was added to the mixture, and the product was extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain crude material. The crude material was purified by column chromatography to provide 55.8 (0.09g, 40.1%). MS (ES): m/z 451.57 [M+H] ⁺ .

Synthesis of compound 55.9. Under a nitrogen atmosphere at 0°C, TFA (0.1 mL) and triethylsilane (0.1 mL) were added to a solution of 55.8 (0.06 g, 0.132 mmol, 1.0 equivalent) in CH ₂ Cl _{2 (2 mL).} The reaction was stirred at room temperature for 2 hours. After completing the reaction, the solvent was removed under reduced pressure to obtain 55.9 (0.05 g, 99.0%). MS (ES): m/z 301.39 [M+H] ⁺ .

Synthesis of compound 55.91. To a mixture of 52.1 (0.02g, 0.052mmol, 1.0 equivalent) in 1,4-dioxane (2mL) was added 55.9 (0.015g, 0.52mmol, 1.0 equivalent) and K ₂ CO ₃ (0.021g, 0.157mmol, 3.0 equivalent). The reaction mixture was degassed with argon for 10 minutes, and then Pd ₂ (dba) ₃ (0.004 g, 0.005 mmol, 0.1 equivalent) and Xantphos (0.006 g, 0.01 mmol, 0.2 equivalent) were added. Degas the suspension for another 5 minutes. The reaction was stirred at 100°C for 2 hours. After completing the reaction, the mixture was poured into water, and the product was extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain pure 55.91 (0.015 g, 40.9%). MS (ES): m/z 583.40 [M+H] ⁺ .

Synthesis of compound I-55. Compound 55.91 (0.015 g, 0.025 mmol, 1.0 equivalent) was dissolved in CH ₂ Cl ₂ (1 mL), and TFA (0.1 mL) was added to the reaction mixture. The reaction was stirred at room temperature for 30 minutes. After completing the reaction, the reaction mixture was poured into water, _{basified with saturated NaHCO 3} and extracted with EtOAc. The organic layers were combined, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain I-55 (0.009 g, 64.2%). MS(ES): m/z 545.59[M+H] ⁺ ; ¹ H NMR (DMSO-d ₆ , 400MHz): δ 9.74(s, 1H), 8.90(s, 1H), 8.58(s, 1H), 8.37-8.36(d, 1H), 7.81-7.78(dd, 1H), 7.62-7.54(m, 1H), 7.28-7.24(t, 2H), 7.17-7.14(d, 1H), 5.70(s, 1H) ), 4.43(s, 2H), 4.17-4.16(d, 2H), 3.76-3.73(t, 2H), 2.19-2.13(s, 2H), 1.67(s, 1H), 1.45(s, 3H), 1.28 (s, 3H), 1.03 (s, 3H).

Example 56. Synthesis of 2-(6-fluoro-2-oxopyridin-1(2H)-yl)-4-((5-morpholin-2-yl)amino)-6,7-di Hydrogen-5H-pyrrolo[3,4-b]pyridin-5-one, I-56

Synthesis of compound 56.2. Metal sodium (2.0 g) was dissolved in tertiary butanol (50 mL) and refluxed for 1 hour. The reaction mixture was cooled to room temperature and 56.1 (5.0 g, 43.85 mmol, 1.0 equivalent) was added. The reaction was stirred at reflux temperature for 12 hours. After completing the reaction, the solvent was removed under reduced pressure. Add ice-cold water and adjust the pH to 3.0 by adding dilute HCl. The product was extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain 56.2 (2.0 g, 40.1%). MS (ES): m/z 113.09 [M+H] ⁺ .

Synthesis of compound 56.4. To a solution of 56.3 (1.0g, 4.55mmol, 1.0 equivalent) in 1,4-dioxane (10mL) was added 56.2 (0.51g, 4.55mmol, 1.0 equivalent) and Cs ₂ CO ₃ (4.43g, 13.63mmol, 3.0 equivalent). The reaction mixture was degassed with argon for 10 minutes, and then Pd ₂ (dba) ₃ (0.415 g, 0.454 mmol, 0.1 equivalent) and Xantphos (0.525 g, 0.91 mmol, 0.2 equivalent) were added. Degas the suspension for another 5 minutes. The reaction was stirred at 100°C for 1 hour. After completing the reaction, the reaction mixture was poured into water, and the product was extracted with EtOAc. The organic layers were combined, washed with brine solution, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain 56.4 (0.40 g, 29.7%). MS (ES): m/z 296.68 [M+H] ⁺ .

Synthesis of compound 56.5. To a solution of 56.4 (0.3g, 1.013mmol, 1.0 equivalent) in dichloroethane (10mL) was added N-bromosuccinimidyl (0.902g, 5.067mmol, 5.0 equivalent) and benzyl peroxide (0.061g) , 0.255mmol, 0.25 equivalent). The reaction was stirred at 100°C for 5 hours. After completing the reaction, the mixture was poured into water, and the product was extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain 56.5 (0.175 g, 46.1%). MS (ES): m/z 375.58 [M+H] ⁺ .

Synthesis of compound 56.6. To a solution of 56.5 (0.175g, 0.466mmol, 1.0 equivalent) in CH ₂ Cl ₂ (3mL) was added 2,4-dimethoxybenzylamine (0.077g, 0.466mmol, 1.0 equivalent) and Et ₃ N (0.094 , 0.933 mmol, 2.0 equivalents). The reaction was stirred at room temperature for 1 hour. After completing the reaction, the mixture was poured into water, and the product was extracted _{with CH 2} Cl _2. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain crude material. The crude material was purified by column chromatography to provide 56.6 (0.09g, 44.9%). MS (ES): m/z 429.83 [M+H] ⁺ .

Synthesis of compound 56.8. To a mixture of 56.6 (0.090g, 0.209mmol, 1.0 equivalent) in 1,4-dioxane (2mL) was added 56.7 ( 0.037g, 0.209mmol, 1.0 equivalent) and K ₂ CO ₃ (0.086g, 0.627mmol, 3.0 equivalent). The reaction mixture was degassed with argon for 10 minutes, and then Pd ₂ (dba) ₃ (0.018 g, 0.020 mmol, 0.1 equivalent) and xantphos (0.023 g, 0.041 mmol, 0.2 equivalent) were added. Degas the suspension for another five minutes. The reaction was stirred at 110°C for 2 hours. After completing the reaction, the mixture was poured into water, and the product was extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain crude material. The crude material was purified by column chromatography to provide 56.8 (0.08g, 66.7%). MS (ES): m/z 572.60 [M+H] ⁺ .

Synthesis of compound I-56. Compound 56.8 (0.08 g, 0.139 mmol, 1.0 equivalent) was dissolved in TFA (2.0 mL). The reaction was stirred at 70°C for 2 hours. After completing the reaction, the mixture was poured into water, _{basified with saturated NaHCO 3} and extracted with EtOAc. The organic layers were combined, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain crude material. The crude material was purified by column chromatography to provide I-56 (0.040 g, 77.5%). MS(ES): m/z 422.42[M+H] ⁺ ; ¹ H NMR (DMSO-d ₆ , 400MHz): δ 9.51 (s, 1H), 8.68 (s, 1H), 8.13-7.97 (m, 3H) ), 7.49-7.46 (dd, 1H), 7.14-7.03 (m, 3H), 4.25 (s, 2H), 3.76-3.73 (t, 4H), 3.12-3.10 (t, 4H).

Example 57. Synthesis of 4-((4-(6-azaspiro[2.5]octane-6-carbonyl)phenyl)amino)-2-(2,6-difluorophenyl)-6,7- Dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, I-57

Synthesis of compound 57.1. At 0°C, to a solution of 6-azaspiro[2.5]octane (0.119g, 0.808mmol, 1.0 equivalent) in THF (3.0mL) was added dropwise 54.1 (0.15g, 0.81mmol, 1.0 equivalent) and Et ₃ N (0.245 g, 2.425 mmol, 3.0 equivalents). The reaction was stirred at room temperature for 2 hours. After the reaction was completed, water was added to the mixture, and the product was extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain crude material. The crude material was purified by trituration with hexane to provide purity 57.1 (0.16 g, 76.0%). MS (ES): m/z 260.29 [M+H] ⁺ .

Synthesis of compound 57.2. Under nitrogen, to a suspension of 10% Pd/C (0.050 g) in MeOH (5 mL) was added a solution of 57.1 (0.16 g, 0.614 mmol, 1.0 equivalent) in MeOH (1 mL). The reaction mixture was purged with hydrogen for 2 hours. After completing the reaction, the mixture was filtered through Celite and washed with MeOH. The resulting filtrate was concentrated under reduced pressure to provide pure 57.2 (0.1 g, 70.6%). MS (ES): m/z 230.31 [M+H] ⁺ .

Synthesis of compound 57.3. To a mixture of 4.4 (0.1g, 0.23mmol, 1.0 equivalent) in 1,4-dioxane ( 2.0mL) was added 57.2 (0.058g, 0.254mmol, 1.1 equivalent) and K ₂ CO ₃ (0.063g, 0.462mmol) , 2.0 equivalent). The reaction mixture was degassed with argon for 10 minutes, and then Pd ₂ (dba) ₃ (0.021 g, 0.023 mmol, 0.1 equivalent) and Xantphos (0.026 g, 0.046 mmol, 0.2 equivalent) were added. Degas the suspension for another 5 minutes. The reaction was stirred at 100°C for 2 hours. After completing the reaction, the mixture was poured into water, and the product was extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain crude material. The crude material was purified by column chromatography to provide 57.3 (0.088g, 60.7%). MS (ES): m/z 624.69 [M+H] ⁺ .

Synthesis of compound I-57. Compound 57.3 (0.088 g, 0.14 mmol, 1.0 equivalent) was dissolved in TFA (2.0 mL). The reaction mixture was stirred at 70°C for 1 hour. After completing the reaction, the mixture was poured into water, _{basified with saturated NaHCO 3} solution and extracted with EtOAc. The organic layers were combined, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain crude material. The crude material was purified by column chromatography to provide I-57 (0.035g, 52.4%). MS(ES): m/z 474.51[M+H] ⁺ ; ¹ H NMR (DMSO-d ₆ , 400MHz): δ 9.16 (s, 1H), 8.76 (s, 1H), 7.57-7.50 (m, 1H) ),7.45-7.39(m,4H),7.24-7.19(m,3H), 4.41(s,2H), 3.67-3.31(m,4H),1.34-1.17(m,4H),0.34(m,4H) ).

Example 58. Synthesis of 4-((4-(3-oxa-9-azaspiro[5.5]undecane-9-carbonyl)phenyl)amine Yl)-2-(2,6-difluorophenyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, I-58

Synthesis of compound 58.1. To a mixture of 52.1 (0.06g, 0.157mmol, 1.0 equivalent) in 1,4-dioxane (2.0mL) was added (4-aminophenyl)(3-oxa-9-azaspiro[5.5] Undecane-9-yl)methanone (0.043 g, 0.157 mmol, 1.0 equivalent) and K ₂ CO ₃ (0.065 g, 0.473 mmol, 3.0 equivalent). The suspension was degassed with argon for 10 minutes, and then Pd ₂ (dba) ₃ (0.014 g, 0.015 mmol, 0.1 equivalent) and Xantphos (0.018 g, 0.031 mmol, 0.2 equivalent) were added. The reaction was stirred at 100°C for 2 hours. After completing the reaction, the mixture was poured into water and extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain crude material. The crude material was purified by column chromatography to provide 58.1 (0.055 g, 56.4%). MS (ES): m/z 618.68 [M+H] ⁺ .

Synthesis of compound I-58. Compound 58.1 (0.055 g, 0.088 mmol, 1.0 equivalent) was dissolved in CH ₂ Cl ₂ (1.0 mL), and TFA (0.5 mL) was added to the reaction. The reaction was stirred at room temperature for 1 hour. After completing the reaction, the mixture was poured into water, _{basified with NaHCO 3} solution, and extracted with CH ₂ Cl ₂ . The organic layers were combined, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain I-58 (0.042 g, 91.1%). MS(ES): m/z 518.56[M+H] ⁺ ; ¹ H NMR (DMSO-d ₆ ,400MHz): 9.21(s,1H), 8.78(s,1H), 7.57-7.53(m,1H) , 7.42 (s, 4H), 7.24-7.19 (m, 3H), 4.42 (s, 2H), 3.55-3.46 (m, 8H), 1.46 (m, 8H).

Example 59. Synthesis of 2-(2,6-difluorophenyl)-4-((5-((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrole-5(3H) -Yl)pyridin-2-yl)amino)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, 1-59

Synthesis of compound 59.1. To a solution of 53.1 (0.2g, 1.40mmol, 1.0 equivalent) in DMSO (2.0mL) was added (3aR,6aS)-hexahydro-1H-furo[3,4-c]pyrrole hydrochloride (0.21g, 1.40mmol, 1.0 equivalent) and DIPEA (2.45ml, 14.07mmol, 10.0 equivalent). The reaction mixture was stirred at 120°C for 1 hour. After completing the reaction, the mixture was poured into water, and the product was extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain 59.1 (0.23 g, 69.5%). MS (ES): m/z 236.17 [M+H] ⁺ .

Synthesis of compound 59.2. Under a nitrogen atmosphere, to a suspension of 10% Pd/C (0.025 g) in MeOH (5.0 mL) was added a solution of 59.1 (0.225 g, 0.957 mmol, 1.0 equivalent) in MeOH (5.0 mL). The suspension was purged with H ₂ gas for 2 hours. After completion of the reaction, the mixture was filtered through Celite, washed with MeOH, and the resulting filtrate was concentrated under reduced pressure to obtain crude 59.2 (0.18 g). MS (ES): m/z 206.26 [M+H] ⁺ .

Synthesis of compound 59.3. To a solution of 52.1 (0.065g, 0.17mmol, 1.0 equivalent) in 1,4-dioxane (2.0mL) was added 59.2 (0.038g, 0.187mmol, 1.1 equivalent) and K ₂ CO ₃ (0.058g, 0.426mmol) , 2.5 equivalents). The reaction mixture was degassed under argon atmosphere for 10 minutes, then Pd ₂ (dba) ₃ (0.015g, 0.017mmol, 0.1 equivalent) and xantphos (0.019g, 0.034mmol, 0.2 equivalent) were added, and the suspension was degassed again Breath for 5 minutes. The reaction was stirred at 100°C for 2 hours. After completing the reaction, the mixture was poured into water, and the product was extracted with EtOAc. The organic layers were combined, washed with brine solution, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain a crude material. The crude material was purified by column chromatography to provide 59.3 (0.065g, 69.7%). MS (ES): m/z 551.5 [M+H] ⁺ .

Synthesis of compound I-59. Compound 59.3 (0.065 g, 0.118 mmol, 1.0 equivalent) was dissolved in CH ₂ Cl ₂ (1.5 mL), and TFA (0.3 mL) was added to the reaction mixture. The reaction was stirred at room temperature for 1 hour. After completing the reaction, the mixture was poured into water, _{basified with NaHCO 3} solution, and extracted with EtOAc. The organic layers were combined, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain a crude material, _{which was purified by trituration with Et 2} O to obtain pure I-59 (0.030 g, 84.7%). MS(ES): m/z 450.37[M+H] ⁺ ; ¹ H NMR (DMSO-d ₆ , 400MHz): δ 9.48(s, 1H), 8.81(s, 1H), 8.28(s1H), 7.79- 7.78(d,1H),7.54-7.61(m,1H),7.28-7.24(t,2H),7.18-7.15(m,1H),7.11-7.09(d,1H), 4.41(s,2H), 3.86-3.83 (t, 2H), 3.52-3.50 (t, 2H), 3.32-3.28 (t, 2H), 3.19-3.17 (d, 2H), 2.98 (bs, 2H).

Example 60. Synthesis of 4-(4-((5-(6-azaspiro[2.5]oct-6-yl)pyridin-2-yl)amino)-5-oxo-6,7-dihydro -5H-pyrrolo[3,4-b]pyridin-2-yl)-3,5-difluorobenzonitrile, I-60

Synthesis of compound 60.2. To a solution of 60.1 (0.070g, 0.155mmol, 1.0 equivalent) in 1,4-dioxane ( 2.0mL) was added 20.3 (0.032g, 0.155mmol, 1.0 equivalent) and K ₂ CO ₃ (0.043g, 0.31mmol) , 2.0 equivalent). The reaction mixture was degassed under an argon atmosphere for 10 minutes, and then Pd ₂ (dba) ₃ (0.014 g, 0.0155 mmol, 0.1 equivalent) and Xantphos (0.018 g, 0.031 mmol, 0.2 equivalent) were added. Degas the suspension again for 5 minutes. The reaction was stirred at 110°C for 1 hour. After completing the reaction, the mixture was poured into water, and the product was extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain crude material. The crude material was purified by column chromatography to provide 60.2 (0.070 g, 70.9%). MS (ES): m/z 572.62 [M+H] ⁺ .

Synthesis of compound I-60. Compound 60.2 (0.070 g, 0.122 mmol, 1.0 equivalent) was dissolved in CH ₂ Cl ₂ (3.0 mL), and TFA (0.4 mL) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 1 hour. After completing the reaction, the mixture was poured into water, _{basified with saturated NaHCO 3} solution and extracted with EtOAc. The organic layers were combined, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain a crude material, which was purified by trituration with n-pentane and ether to obtain pure I-60 (0.047 g, 81.4%). MS(ES): m/z 472.50[M+H] ⁺ ; ¹ H NMR (DMSO-d ₆ , 400MHz): δ 9.55(s, 1H), 8.85(s, 1H), 8.39(s, 1H), 8.03(d,1H),7.99-7.97(d,2H),7.49-7.46(dd,1H),7.11-7.09(d,1H), 4.41(s,2H), 3.20-3.17(t,4H), 1.46-1.40 (t, 4H), 0.329 (s, 4H).

Example 61. Synthesis of 2-(2,6-difluorophenyl)-4-((1-hydroxy-1,3-dihydro-benzo-[c][1,2]oxaborole -5-yl)amino)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, I-61

Synthesis of compound 61.2. Dissolve bis(pinacol) diborate (0.9g, 3.46mmol, 1.0 equivalent), PdCl ₂ (dppf) (0.277g, 0.346mmol, 0.1 equivalent) and AcOK (1.018g, 10.38mmol, 3.0 equivalent) in 1,4-dioxane (10 mL). The suspension was degassed with argon, and then a solution of 61.1 (0.9 g, 3.46 mmol, 1.0 equivalent) in 1,4-dioxane (8.0 mL) was added. The reaction mixture was stirred at 70°C for 3 hours. After completing the reaction, the solid was filtered and the solvent was removed under reduced pressure. The crude material was suspended in water and then extracted with EtOAc. The organic layers were combined, washed with brine solution, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain 61.2 (0.40 g, 37.6%).

Synthesis of compound 61.3. At 0°C, compound 61.2 (0.4 g, 1.30 mmol, 1.0 equivalent) and DIBAL (5 ml, 0.51 mmol, 5.0 equivalent) were dissolved in CH ₂ Cl ₂ (2.0 mL). The reaction was stirred at 0 to 5°C for 4 hours. After the reaction was completed, MeOH was added and the reaction mixture was stirred for 20 minutes. Dilute HCl was added, and the product was extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain crude 61.3 (0.36 g, 99.0%), which was used in the next step without purification.

Synthesis of compound 61.4. Compound 61.3 (0.36 g, 1.43 mmol, 1.0 equivalent) was dissolved in 6M HCl (30 mL), and the reaction was stirred at 80° C. for 24 hours. After the reaction was completed, water was added to the reaction mixture, and the product was extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain 1.3 (0.1 g, 43.3%).

Synthesis of compound 61.5. Under nitrogen, to a suspension of 10% Pd/C (0.25 g) in MeOH (5.0 mL) was added a solution of 61.4 (0.1 g, 0.3 mmol, 1.0 equivalent) in MeOH (3.0 mL). The suspension was purged with H ₂ gas for 1 hour. After completing the reaction, the mixture was filtered through Celite, washed with MeOH, and the resulting filtrate was concentrated under reduced pressure to obtain a crude material. The crude material was purified by trituration with n-hexane and Et ₂ O to provide 61.5 (0.060 g, 72.1%).

Synthesis of compound 61.6. To a mixture of 52.1 (0.06g, 0.157mmol, 1.0 equivalent) in 1,4-dioxane (2.5mL) was added 61.5 (0.025g, 0.157mmol, 1.0 equivalent) and K ₂ CO ₃ (0.067g, 0.471mmol) , 3.0 equivalents). The mixture was degassed with argon for 10 minutes, and then Pd ₂ (dba) ₃ (0.014 g, 0.015 mmol, 0.1 equivalent) and Xantphos (0.016 g, 0.031 mmol, 0.2 equivalent) were added. Degas the suspension for another 5 minutes. The reaction was stirred at 100°C for 2 hours. After completing the reaction, the mixture was poured into water, and the product was extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain crude material. The crude material was purified by column chromatography to obtain 61.6 (0.027 g, 34.7%).

Synthesis of compound I-61. Compound 61.6 (0.027 g, 0.054 mmol, 1.0 equivalent) was dissolved in CH ₂ Cl ₂ (2.0 mL), and TFA (0.5 mL) was added to the reaction mixture. The reaction was stirred at room temperature for 1 hour. After completing the reaction, the mixture was poured into water, _{basified with saturated NaHCO 3} solution, and extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain crude material. The crude material was purified by column chromatography to provide I-61 (0.006g, 27.9%). ¹ H NMR (DMSO-d ₆ , 400MHz): δ 9.12 (s, 1H), 8.61 (s, 1H), 7.48-7.37 (m, 4H), 7.08-7.03 (m, 3H), 4.26 (s, 2H) ), 4.12(s, 2H).

Example 62. Synthesis of 4-((5-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)pyridin-2-yl)amino)-2-(2,6- Difluorophenyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, I-62

Synthesis of compound 62.1. To a solution of 53.1 (0.3g, 2.11mmol, 1.0 equivalent) in DMSO (10mL) was added 1,4-dioxa-8-azaspiro[4.5]decane (0.30g, 2.11mmol, 1.0 equivalent) And DIPEA (3.63ml, 21.1mmol, 10.0 equivalent). The reaction mixture was stirred at 100°C for 2 hours. After completion, the reaction was quenched with water and the product was extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain pure 62.1 (0.50 g, 89.3%). MS (ES): m/z 265.27 [M+H] ⁺ .

Synthesis of compound 62.2. Under nitrogen, to a suspension of 10% Pd/C (0.150 g) in MeOH (3.5 mL) was added a solution of 62.1 (0.5 g, 1.88 mmol, 1.0 equivalent) in MeOH (3.5 mL). The suspension was purged with H ₂ gas for 2 hours. After completing the reaction, the mixture was filtered through Celite and washed with MeOH. The solvent was removed under reduced pressure, and the crude material was purified by trituration with n-pentane to obtain 62.2 (0.41 g, 92.5%). MS (ES): m/z 235.29 [M+H] ⁺ .

Synthesis of compound 62.3. To a solution of 52.1 (0.07g, 0.184mmol, 1.0 equivalent) in 1,4-dioxane (3.0mL) was added 62.2 (0.043g, 0.184mmol, 1.1 equivalent) and K ₂ CO ₃ (0.05g, 0.368mmol) , 2.0 equivalent). The suspension was degassed with argon for 10 minutes, and then Pd ₂ (dba) ₃ (0.016 g, 0.018 mmol, 0.1 equivalent) and Xantphos (0.021 g, 0.036 mmol, 0.2 equivalent) were added. In addition, after purging with argon (5 minutes), the reaction was stirred at 100°C for 2 hours. After completing the reaction, the mixture was poured into water, and the mixture was extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain crude material. The crude material was purified by column chromatography to obtain 62.3 (0.068 g, 63.8%). MS (ES): m/z 579.60 [M+H] ⁺ .

Synthesis of compound I-62. Compound 62.3 (0.068 g, 0.117 mmol, 1.0 equivalent) was dissolved in CH ₂ Cl ₂ (2.0 mL), and TFA (0.3 mL) was added to the reaction mixture. The reaction was stirred at room temperature for 1 hour. After completing the reaction, the mixture was poured into water, _{basified with saturated NaHCO 3} solution and extracted with EtOAc. The organic layers were combined, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain a crude material. The crude material was purified by column chromatography to provide I-62 (0.039g, 69.3%). MS(ES): m/z 479.49[M+H] ⁺ ; ¹ H NMR (DMSO-d ₆ , 400MHz): δ 9.51(s, 1H), 8.80(s, 1H), 8.37(s, 1H), 8.05-8.04(d,1H),7.60-7.53(m,1H),7.49-7.46(dd,1H),7.28-7.22(m,2H),7.15-7.07(m,1H),4.40(s,2H) ), 3.90 (m, 4H), 3.24-3.18 (m, 4H), 1.71-1.69 (t, 4H).

Example 63. Synthesis of 2-(2,6-difluorophenyl)-4-((4-((3aR,6aS)-hexahydro-1H-furo[3,4-c]pyrrole-5-carbonyl) (Phenyl)amino)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, I-63

Synthesis of compound 63.1. To a solution of 54.2 (0.124g, 0.668mmol, 1.0 equivalent) in THF (3.0mL) was added dropwise Et ₃ N (0.202g, 2.0mmol, 3.0 equivalent) and (3aR, 6aS)-hexahydro-1H-furan And [3,4-c]pyrrole (0.1 g, 0.668 mmol, 1.0 equivalent). The reaction was stirred at room temperature for 2 hours. After completing the reaction, _{the mixture was quenched with saturated NaHCO 3} solution, and the product was extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain pure 63.1 (0.09 g, 53.1%). MS (ES): m/z 262.27 [M+H] ⁺ .

Synthesis of compound 63.2. Under N ₂ , to a suspension of 10% Pd/C (0.050 g) in MeOH (3.5 mL) was added a solution of 63.1 (0.09 g, 0.343 mmol, 1.0 equivalent) in MeOH (2.5 mL). The suspension was purged with H ₂ gas for 1 hour. After completing the reaction, the mixture was filtered through Celite and washed with MeOH. The filtrate obtained was concentrated under reduced pressure to obtain pure 63.2 (0.06 g, 75.3%). MS (ES): m/z 232.28 [M+H] ⁺ .

Synthesis of compound 63.3. To a solution of 52.1 (0.065g, 0.17mmol, 1.0 equivalent) in 1,4-dioxane ( 2.0mL) was added 63.2 (0.040g, 0.171mmol, 1.0 equivalent) and K ₂ CO ₃ (0.047g, 0.342mmol) , 2.0 equivalent). The reaction mixture was degassed with argon for 10 minutes, and then Pd ₂ (dba) ₃ (0.015 g, 0.017 mmol, 0.1 equivalent) and Xantphos (0.020 g, 0.034 mmol, 0.2 equivalent) were added. The reaction was stirred at 100°C for 2 hours. After completing the reaction, the mixture was poured into water, and the product was extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain crude material. The crude material was purified by column chromatography to provide 63.3 (0.065g, 66.0%). MS(ES): m/z 576.60 [M+H] ⁺ .

Synthesis of compound I-63. Compound 63.3 (0.065 g, 0.112 mmol, 1.0 equivalent) was dissolved in CH ₂ Cl ₂ (3.0 mL), and TFA (0.3 mL) was added to the reaction mixture. The reaction was stirred at room temperature for 1 hour. After completing the reaction, the mixture was poured into water, _{basified with saturated NaHCO 3} and extracted with EtOAc. The organic layers were combined, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain crude material. The crude material was purified by trituration with n-pentane and Et ₂ O to obtain pure I-63 (0.040 g, 74.5%). MS(ES): m/z 476.48[M+H] ⁺ ; ¹ H NMR (DMSO-d ₆ , 400MHz): δ 9.17(s, 1H), 8.78(s, 1H), 7.56-7.50 (m, 3H ), 7.42-7.40 (d, 2H), 7.24-7.20 (t, 3H), 4.41 (s, 2H), 3.71 (m, 4H), 3.46 (m, 4H), 2.89 (m, 2H).

Example 64. Synthesis of 6-((2-(2,6-difluorophenyl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-4-yl )Amino)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one, I-64

Synthesis of compound 64.2. At 0°C, 2-methanesulfonic acid (3.1 ml, 47.39 mmol, 10.0 equivalent) was added to a mixture of 64.1 (1.0 g, 4.74 mmol, 1.0 equivalent) in CH ₂ Cl ₂ (10.0 mL). Sodium azide (0.62 g, 9.48 mmol, 2.0 equivalents) was added slowly in portions. After the addition was complete, the mixture was stirred for an additional 12 hours. After completing the reaction, NaOH (20%) aqueous mixture was added until the mixture was slightly alkaline. The mixture was extracted with CH ₂ Cl _2. The organic layers were combined, and the solvent was evaporated under reduced pressure. The crude material was purified by column chromatography to provide 64.2 (0.5 g, 46.7%). MS (ES): m/z 226.07 [M+H] ⁺ .

Synthesis of compound 64.3. Compound 64.2 (0.5 g, 2.21 mmol, 1.0 equivalent) was dissolved in DMF (3.5 mL), and NaH (0.076 g, 3.32 mmol, 1.5 equivalent) was added to the reaction mixture at 0°C. At 0°C, methyl iodide (0.47 g, 3.32 mmol, 1.5 equivalents) was added dropwise to the reaction mixture. The reaction was stirred at 0°C for 1 hour. After completing the reaction, the mixture was quenched with 2N HCl solution, and the product was extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain crude material. The crude material was purified by column chromatography to provide 64.3 (0.25 g, 47.1%). MS (ES): m/z 240.10 [M+H] ⁺ .

Synthesis of compound 64.4. To a solution of compound 64.3 (0.25g, 1.04mmol, 1.0 equivalent) in toluene (1.0mL) was added benzophenone imine (0.21g, 1.14mmol, 1.1 equivalent) and NaOBu ^t (0.15g, 1.56mmol, 1.5 equivalent) ). The reaction mixture was degassed with argon for 10 minutes, and then Pd ₂ (dba) ₃ (0.009 g, 0.01 mmol, 0.01 equivalent) and BINAP (0.029 g, 0.052 mmol, 0.05 equivalent) were added. Then the reaction was heated at 100°C for 8 hours. After completion, the reaction mixture was poured into water, and the product was extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain crude material. The crude material was purified by column chromatography to provide 64.4 (0.04g, 21.8%). MS (ES): m/z 176.22 [M+H] ⁺ .

Synthesis of compound 64.5. To a mixture of 52.1 (0.060g, 0.157mmol, 1.0 equivalent) in 1,4-dioxane (1.5mL) was added 64.4 (0.027g, 0.157mmol, 1.0 equivalent) and K ₂ CO ₃ (0.065g, 0.47mmol) , 3.0 equivalents). The reaction mixture was degassed with argon for 10 minutes, and then Pd ₂ (dba) ₃ (0.014 g, 0.015 mmol, 0.1 equivalent) and Xantphos (0.018 g, 0.031 mmol, 0.2 equivalent) were added. Degas the suspension again for 5 minutes. The reaction was stirred at 100°C for 2 hours. After completing the reaction, the mixture was poured into water, and the product was extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain crude material. The crude material was purified by column chromatography to provide 64.5 (0.038 g, 46.3%). MS (ES): m/z 520.54 [M+H] ⁺ .

Synthesis of compound I-64. Compound 64.5 (0.038 g, 0.073 mmol, 1.0 equivalent) was dissolved in CH ₂ Cl ₂ (1.0 mL), and TFA (0.5 mL) was added to the reaction mixture. The reaction was stirred at room temperature for 1 hour. After completing the reaction, the mixture was poured into water, _{basified with saturated NaHCO 3} solution, and the product was extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain crude material. The crude material was purified by column chromatography to provide I-64 (0.023 g, 74.9%). MS(ES): m/z 420.42[M+H] ⁺ ; ¹ H NMR (DMSO-d ₆ , 400MHz): δ 9.23 (s, 1H), 8.80 (s, 1H), 7.86-7.84 (d, 1H) ), 7.56-7.52 (m, 1H), 7.33-7.20 (m, 5H), 4.41 (s, 2H), 3.55-3.51 (t, 2H), 3.00 (s, 3H), 2.99-2.95 (t, 2H) ).

Example 65. Synthesis of 4-((5-(2,5-dioxa-8-azaspiro[3.4]oct-8-yl)pyridin-2-yl)amino)-2-(2,6- Difluorophenyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, I-65

Synthesis of compound 65.2. At room temperature, to a stirred solution of 2-aminoethane-1-ol (1.0 g, 16.37 mmol, 1.0 equivalent) in CH ₂ Cl ₂ (10.0 mL) was added 65.1 (1.29 g, 18.0 mmol, 1.1 equivalent) ), AcOH (0.098g, 1.64mmol, 0.1 equivalent) and molecular sieve (1.0g). The reaction was stirred at room temperature for 3 hours. After completing the reaction, the mixture was filtered and concentrated under reduced pressure. The crude material was purified by column chromatography to provide 65.2 (0.54 g, 33.8%). MS (ES): m/z 115.13 [M+H] ⁺ .

Synthesis of compound 65.3. To a solution of 20.1 (0.5g, 2.46mmol, 1.0 equivalent) in 1,4-dioxane (8.0mL) was added compound 65.2 (0.283g, 2.46mmol, 1.0 equivalent) and NaOBu ^t (0.472g, 4.92mmol, 2.0 equivalent). The reaction mixture was degassed with argon for 15 minutes. _{Then Pd 2} (dba) ₃ (0.023 g, 0.246 mmol, 0.1 equivalent) and Devphos (0.193 g, 0.492 mmol, 0.2 equivalent) were added to the reaction mixture. The reaction mixture was irradiated in a microwave at 100°C for 2 hours. After completing the reaction, the mixture was quenched with water, and the product was extracted with EtOAc. The organic layers were combined, washed with brine, and concentrated under reduced pressure to obtain a crude material. The crude material was purified by column chromatography to provide 65.3 (0.165 g, 28.2%). MS (ES): m/z 237.22 [M+H] ⁺ .

Synthesis of compound 65.4. Under N ₂ , to a suspension of 10% Pd/C (0.030 g) in MeOH (2.0 mL) was added a solution of 65.3 (0.165 g, 0.695 mmol, 1.0 equivalent) in MeOH (2.0 mL). Purify the suspension with hydrogen for 1 hour. After completing the reaction, the mixture was filtered through Celite and washed with MeOH. The filtrate obtained was concentrated under reduced pressure and triturated with pentane to obtain 65.4 (0.14 g, 97.1%). MS (ES): m/z 207.23 [M+H] ⁺ .

Synthesis of compound 65.6. Under a nitrogen atmosphere, to a suspension of 10% Pd/C (0.030 g) in MeOH (2.0 mL) was added a solution of 65.3 (0.165 g, 0.695 mmol, 1.0 equivalent) in MeOH (2.0 mL). The suspension was purged with H ₂ gas for 1 hour. After completing the reaction, the mixture was filtered through Celite and washed with MeOH. The solvent was removed under reduced pressure, and the crude material was triturated with pentane to obtain pure 65.6 (0.14 g, 97.1%). MS (ES): m/z 207.23 [M+H] ⁺ .

Synthesis of compound I-65. Compound 65.6 (0.04 g, 0.07 mmol, 1.0 equivalent) was dissolved in a THF/MeOH mixture (4:1), and LiOH (0.011 g, 0.282 mmol, 4.0 equivalent) in water (1.0 mL) was added. The reaction was stirred at room temperature for 1 hour. After completing the reaction, the mixture was poured into water, _{basified with saturated NaHCO 3} solution, and the product was extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain crude material. The crude material was purified by trituration with Et ₂ O to obtain pure I-65 (0.022 g, 68.9%). MS(ES): m/z 451.43[M+H] ⁺ ; ¹ H NMR (DMSO-d ₆ , 400MHz): δ 9.54(s, 1H), 8.83(s, 1H), 8.38(s, 1H), 8.06 (d, 1H), 7.58-7.55 (m, 2H), 7.27-7.22 (m, 3H), 5.04-5.02 (d, 2H), 4.69-4.67 (d, 2H), 4.41 (s, 2H), 4.05-4.03 (m, 2H), 3.47-3.44 (m, 2H).

Example 66. Synthesis of 2-(2,6-difluorophenyl)-4-((4-(1,1,1,3,3,3-hexafluoro-2-hydroxy-prop-2-yl)benzene (Amino)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, 1-66

Synthesis of compound 66.1. To a mixture of 52.1 (0.070g, 0.184mmol, 1.0 equivalent) in 1,4-dioxane (3.0mL) was added 2-(4-aminophenyl)-1,1,1,3,3,3 -Hexafluoropropan-2-ol (0.048 _{g, 0.184 mmol, 1.0 equivalent) and K 2} CO ₃ (0.051 g, 0.368 mmol, 2.0 equivalent). The suspension was degassed with argon for 10 minutes, and then Pd ₂ (dba) ₃ (0.017 g, 0.018 mmol, 0.1 equivalent) and Xantphos (0.021 g, 0.036 mmol, 0.2 equivalent) were added. Degas the suspension for another 5 minutes. The reaction was stirred at 100°C for 2 hours. After completing the reaction, the mixture was poured into water, and the product was extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain crude material. The crude material was purified by column chromatography to provide 66.1 (0.064 g, 57.7%). MS (ES): m/z 603.47 [M+H] ⁺ .

Synthesis of compound I-66. At 0°C, to a solution of 66.1 (0.064 g, 0.106 mmol, 1.0 equivalent) in CH ₂ Cl ₂ (1.5 mL) was added TFA (0.3 mL). The reaction mixture was stirred at room temperature for 1 hour. After completing the reaction, the mixture was poured into water, _{basified with saturated NaHCO 3} and extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain a crude material, which was purified by trituration _{with Et 2} O to obtain I-66 (0.038 g, 71.8%). MS(ES): m/z 503.35[M+H] ⁺ ; ¹ H NMR (DMSO-d ₆ , 400MHz): δ 9.22(s, 1H), 8.79(s, 1H), 8.71(s, 1H), 7.69-7.66 (d, 2H), 7.58-7.51 (m, 3H), 7.24-7.19 (m, 3H), 4.41 (s, 2H).

Example 67. Synthesis of 2-(4-((2-(2,6-difluorophenyl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine- 4-yl)amino)phenyl)-N-ethyl-2-methylpropanamide, I-67

Synthesis of compound 67.1. At 0°C, to a solution of NaOBu ^t (1.45 g, 15.0 mmol, 1.05 equivalent) in DMF (50 mL) was added 39.1 (3.0 g, 14.3 mmol, 1.0 equivalent). After stirring for 5 minutes, MeI (2.12 g, 15.0 mmol, 1.05 equivalents) was added dropwise, and the reaction mixture was stirred at 0°C for 30 minutes. After 5 minutes, a second portion of NaOBu ^t (1.45 g, 15.0 mmol, 1.05 equivalent) was added at 0° C., and the reaction was stirred for 5 minutes. Finally, a second portion of MeI (2.12 g, 15.0 mmol, 1.05 equivalents) was added dropwise, and the reaction was stirred at 0°C for 30 minutes. After completion, the reaction was quenched with dilute AcOH, and the product was extracted with EtOAc. The organic layer was separated, washed with brine solution, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain 67.1 (2.0 g, 58.8%). MS (ES): m/z 237.26 [M+H] ⁺ .

Synthesis of compound 67.2. To a solution of 67.1 (0.4g, 1.68mmol, 1.0 equivalent) in THF (4.0mL) was added ethylamine (1.68ml, 3.37mmol, 2.0 equivalent) and DIPEA (0.6ml, 3.36mmol, 2.0 equivalent). The reaction was cooled to 0°C. At 0°C, trimethylaluminum (4.2 ml, 8.4 mmol, 5.0 equivalents) was added dropwise to the mixture, and then the reaction was stirred at reflux temperature for 6 hours. After completion, the reaction mixture was quenched with ice-cold NaHCO ₃ solution, and the product was extracted with EtOAc. The organic layer was separated, washed with brine solution, and concentrated under reduced pressure to obtain a crude material. The crude material was purified by column chromatography to provide 67.2 (0.24 g, 61.0%). MS (ES): m/z 236.27 [M+H] ⁺ .

Synthesis of compound 67.3. Under nitrogen, to a suspension of 10% Pd/C (0.05 g) in MeOH (2.0 mL) was added a solution of 67.2 (0.243 g, 1.028 mmol, 1.0 equivalent) in MeOH (2.0 mL). Hydrogen gas was bubbled into the reaction mixture at room temperature for 1 hour. After completing the reaction, the mixture was filtered through Celite, washed with MeOH, and the resulting filtrate was concentrated under reduced pressure, and then triturated with pentane to obtain pure 67.3 (0.19 g, 89.6%). MS (ES): m/z 206.29 [M+H] ⁺ .

Synthesis of compound 67.4. To a mixture of 67.3 (0.1g, 0.26mmol, 1.0 equivalent) in 1,4-dioxane (3.0mL) was added compound 67.3 (0.06g, 0.28mmol, 1.0 equivalent) and K ₂ CO ₃ (0.090g, 0.65 mmol, 2.5 equivalents). The reaction mixture was degassed with argon for 10 minutes, then Pd ₂ (dba) ₃ (0.024 g, 0.026 mmol, 0.1 equivalent) and Xanthpos (0.03 g, 0.052 mmol, 0.2 equivalent) were added, and degassed again for 5 minutes. The reaction was stirred at 100°C for 2 hours. After completing the reaction, the mixture was poured into water, and the product was extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain 67.4 (0.127 g, 87.8%). MS (ES): m/z 550.61 [M+H] ⁺ .

Synthesis of compound I-67. To a solution of 67.4 (0.127 g, 0.23 mmol, 1.0 equivalent) in CH ₂ Cl ₂ (2.0 mL) was added TFA (0.5 mL). The reaction mixture was stirred at room temperature for 1 hour. After completing the reaction, _{the mixture was basified with saturated NaHCO 3} solution and extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain crude material, which was purified by column chromatography and triturated with Et ₂ O to obtain pure I-67 (0.069g, 66.4%). MS(ES): m/z 450.49[M+H] ⁺ ; ¹ H NMR (DMSO-d ₆ , 400MHz): δ 8.96(s, 1H), 8.71(s, 1H), 7.52(m, 1H), 7.37-7.31(m,5H),7.22-7.18(t,2H),7.02(s,1H), 4.38(s,2H),3.05-3.02(q,2H),1.42(s,6H),0.95- 0.92(t,3H).

Example 68. Synthesis of 4-(benzo[d][1,3]dioxol-5-ylamino)-2-(2,6-difluorophenyl)-6,7-dihydro -5H-pyrrolo[3,4-b]pyridin-5-one, I-68

Synthesis of compound 68.1. To a suspension of 52.1 (0.105g, 0.394mmol, 1.0 equivalent) in 1,4-dioxane (2.0mL) was added benzo[d][1,3]dioxol-5-amine ( 0.054 g, 0.394 mmol, 1.0 equivalent) and K ₂ CO ₃ (0.11 g, 0.79 mmol, 2.0 equivalent). The reaction was degassed with argon, and then Pd ₂ (dba) ₃ (0.036 g, 0.039 mmol, 0.1 equivalent) and Xantphos (0.045 g, 0.078 mmol, 0.2 equivalent) were added. The reaction was stirred at 100°C for 2 hours. After completing the reaction, the mixture was poured into water, and the product was extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain crude material. The crude material was purified by column chromatography to provide 68.1 (0.105 g, 55.4%). MS (ES): m/z 481.46 [M+H] ⁺ .

Synthesis of compound I-68. To a solution of 68.1 (0.10 g, 0.207 mmol, 1.0 equivalent) in CH ₂ Cl ₂ (2.0 mL) at 0° C. under nitrogen, TFA (0.3 mL) was added dropwise. The reaction was stirred at room temperature for 1 hour. After completing the reaction, the mixture was poured into water, _{basified with saturated NaHCO 3} solution and extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain crude material. The crude material was purified by trituration with pentane to obtain pure I-68 (0.075 g, 94.7%). MS(ES): m/z 381.34[M+H] ⁺ ; ¹ H NMR (DMSO-d ₆ , 400MHz): δ 8.74(s, 1H), 8.65(s, 1H), 7.53-7.49(m, 1H ), 7.21-7.17 (t, 2H), 6.98-6.92 (m, 2H), 6.82-6.79 (m, 2H), 6.04 (s, 2H), 4.37 (s, 2H).

Example 69. Synthesis of 4-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)amino)-2-(2,6-difluoro-benzene Yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, I-69

Synthesis of compound 69.2. Under nitrogen, to a suspension of 10% Pd/C (0.05 g) in MeOH (5.0 mL) was added a solution of 69.1 (0.5 g, 2.46 mmol, 1.0 equivalent) in MeOH (3.0 mL). The reaction was purged with H ₂ gas for 2 hours. After completing the reaction, the mixture was filtered through Celite and washed with MeOH. The resulting filtrate was concentrated under reduced pressure to obtain a crude material, which was triturated with n-hexane to obtain 69.2 (0.31 g, 72.5%). MS (ES): m/z 173.12 [M+H] ⁺ .

Synthesis of compound 65.5. A solution of NaH (0.01, 3.57 mmol, 2.0 equivalents) in THF (10 mL) was cooled to 0°C. Compound 69.3 (0.5 g, 1.78 mmol, 1.0 equivalent) was added and stirred at 0°C. Methyl pivaloyl chloride (0.321 g, 2.14 mmol, 1.2 equivalents) was added dropwise and the reaction was stirred at room temperature for 4 hours. After completion, the reaction was quenched with water. The product was extracted with EtOAc and washed with NaHCO ₃ solution. The organic layer was separated, washed with brine, dried over Na ₂ SO _4, and concentrated under reduced pressure to give the crude material. The crude material was purified by column chromatography to provide 65.5 (0.34g, 58.4%). MS (ES): m/z 326.62 [M+H] ⁺ .

Synthesis of compound 69.4. To a solution of compound 65.5 (0.12g, 0.225mmol, 1.0 equivalent) in 1,4-dioxane ( 3.0mL) was added compound 69.2 (0.039g, 0.223mmol, 1.0 equivalent) and K ₂ CO ₃ (0.077g, 0.564 mmol, 2.5 equivalents). The suspension was degassed with argon for 10 minutes, then Pd ₂ (dba) ₃ (0.021 g, 0.023 mmol, 0.1 equivalent) and Xantphos (0.026 g, 0.045 mmol, 0.2 equivalent) were added, and degassed again for 5 minutes. The reaction was stirred at 100°C for 2 hours. After completing the reaction, the mixture was poured into water and extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain 69.4 (0.12 g, 69.3%). MS (ES): m/z 463.28 [M+H] ⁺ .

Synthesis of compound I-69. To a solution of compound 69.4 (0.12 g, 0.25 mmol, 1.0 equivalent) in CH ₂ Cl ₂ (3.0 mL) was added TFA (1.5 mL). The reaction was stirred at room temperature for 1 hour. After completing the reaction, the mixture was poured into water, _{basified with saturated NaHCO 3} and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine solution, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain 61.2 (0.037 g, 34.8%). MS(ES): m/z 417.32[M+H] ⁺ ; ¹ H NMR (DMSO-d ₆ , 400MHz): δ 8.98(s, 1H), 8.71(s, 1H), 7.54-7.41(m, 3H ), 7.21-7.17 (m, 3H), 6.97 (s, 1H), 4.39 (s, 2H).

Example 70. Synthesis of 2-(2,6-difluorophenyl)-4-((3,3-dimethyl-2,3-dihydrobenzofuran-6-yl)amino)-6,7 -Dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, I-70

Synthesis of compound 70.1. To a mixture of 52.1 (0.1g, 0.26mmol, 1.0 equivalent) in 1,4-dioxane (3.0mL) was added 3,3-dimethyl-2,3-dihydrobenzofuran-6-amine ( 0.042 g, 0.262 mmol, 1.0 equivalent) and K ₂ CO ₃ (0.09 g, 0.657 mmol, 2.5 equivalent). The reaction mixture was degassed with argon for 10 minutes, and then Pd ₂ (dba) ₃ (0.024 g, 0.026 mmol, 0.1 equivalent) and Xantphos (0.030 g, 0.052 mmol, 0.2 equivalent) were added. The suspension was then degassed for another 5 minutes. The reaction was then heated at 100°C for 2 hours. After completing the reaction, the mixture was poured into water, and the product was extracted with EtOAc. The organic layers were combined, washed with brine solution, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain a crude material. This crude material was purified by column chromatography to provide 70.1 (0.076 g, 57.0%). MS (ES): m/z 507.54 [M+H] ⁺ .

Synthesis of compound I-70. To a solution of 70.1 (0.076 g, 0.149 mmol, 1.0 equivalent) in CH ₂ Cl ₂ (3.0 mL) was added TFA (1.0 mL). The reaction was stirred at room temperature for 1 hour. After completing the reaction, the mixture was poured into water, _{basified with saturated NaHCO 3} solution, and the product was extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain crude material. The crude material was purified by column chromatography and grinding to provide I-70 (0.05g, 82.0%). MS(ES): m/z 407.42[M+H] ⁺ ; ¹ H NMR (DMSO-d ₆ , 400MHz): δ 8.88 (s, 1H), 8.69 (s, 1H), 7.56-7.49 (m, 1H) ), 7.23-7.18 (m, 3H), 7.00 (s, 1H), 6.85-6.82 (dd, 1H), 6.78-6.77 (d, 1H), 4.37 (s, 2H) 4.23 (s, 2H), 1.28 (s,6H).

Example 71. Synthesis of 2-(2,6-difluorophenyl)-4-((2,2-dimethyl-2,3-dihydrobenzofuran-6-yl)amino)-6,7 -Dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, I-71

Synthesis of compound 71.2. At room temperature, to a mixture of 71.1 (2.13 g, 12.3 mmol, 1.0 equivalent) and K ₂ CO ₃ (3.4 g, 24.6 mmol, 2.0 equivalent) in DMF (10 mL) was added 3-bromo-2-methylpropane -1-ene (2.0 g, 14.8 mmol, 1.2 equivalents). The reaction mixture was stirred at 80°C for 3 hours. After completing the reaction, the mixture was poured into water and extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain 71.2 (2.9 g, 99.0%). MS (ES): m/z 227.10 [M+H] ⁺ .

Synthesis of compound 71.3. A solution of 71.2 (2.9 g, 12.8 mmol, 1.0 equivalent) in N,N-diethylaniline (10 mL) was stirred at 210 to 220°C under argon for 12 hours. After completing the reaction, the mixture was cooled to room temperature, acidified with 1N HCl, and extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain crude material. The crude material was purified by column chromatography to provide 71.3 (0.55 g, 18.9%). MS (ES): m/z 227.10 [M+H] ⁺ .

Synthesis of compound 71.4. To a solution of compound 71.3 (0.55 g, 2.43 mmol, 1.0 equivalent) in anhydrous toluene (6.0 mL) was added p-toluenesulfonic acid (46 mL). The reaction mixture was stirred at 100°C for 2 hours. After completing the reaction, the mixture was cooled to room temperature, and basified with 1N NaOH solution, and extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain 71.4 (0.45 g, 81.8%). MS (ES): m/z 227.10 [M+H] ⁺ .

Synthesis of compound 71.5. To a solution of 71.4 (0.25g, 1.10mmol, 1.0 equivalent) in THF (5.0mL) was added CyJohnphos (0.077g, 0.22mmol, 0.2 equivalent) and Pd ₂ (dba) ₃ (0.1g, 0.11mmol, 0.1 equivalent) . The suspension was degassed with argon, LHMDS (0.919 g, 5.50 mmol, 5.0 equivalents) was added, and the mixture was stirred at 100°C for 2 hours. After completing the reaction, the mixture was poured into dilute HCl and extracted with EtOAc. The aqueous fraction was basified with saturated NaHCO ₃ solution and extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain crude material. The crude material was purified by column chromatography to provide 71.5 (0.087g, 48.4%). MS(ES): m/z 163.22 [M+H] ⁺ .

Synthesis of compound 71.6. To a mixture of 52.1 (0.11g, 0.29mmol, 1.15 equivalents) in 1,4-dioxane (2.5mL) was added compound 1.4 (0.042g, 0.251mmol, 1.0 equivalent) and K ₂ CO ₃ (0.069g, 0.502 mmol, 2.0 equivalents). The reaction mixture was degassed with argon for 10 minutes, then Pd ₂ (dba) ₃ (0.023 g, 0.021 mmol, 0.1 equivalent) and Xantphos (0.029 g, 0.050 mmol, 0.2 equivalent) were added, and degassed again for 5 minutes. The reaction was stirred at 100°C for 2 hours. After completing the reaction, the mixture was poured into water and extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain crude material. The crude material was purified by column chromatography to provide 71.6 (0.095g, 64.8%). MS (ES): m/z 507.54 [M+H] ⁺ .

Synthesis of compound I-71. To a solution of compound 71.6 (0.095 g, 0.187 mmol, 1.0 equivalent) in CH ₂ Cl ₂ (2.0 mL) was added TFA (0.5 mL). The reaction was stirred at room temperature for 1 hour. After completing the reaction, the mixture was poured into water, _{basified with saturated NaHCO 3} and extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain I-71 (0.041 g, 53.8%). MS(ES): m/z 407.42[M+H] ⁺ ; ¹ H NMR (CDCl ₃ , 400MHz): δ 8.67 (s, 1H), 7.39-7.31 (m, 1H), 7.14-7.10 (m, 2H) ), 7.02-6.96(m, 2H), 6.77-6.74(dd, 1H), 6.71-6.70(d, 1H), 5.98(s, 1H), 4.50(s, 2H), 3.01(s, 2H), 1.50(s, 6H).

Example 72. Synthesis of 2-(2,6-difluorophenyl)-4-((4-oxochroman-7-yl)amino)-6,7-dihydro-5H-pyrrolo[3, 4-b]pyridin-5-one, I-72

Synthesis of compound 72.2. At 0°C, to a solution of 72.1 (1.0 g, 6.7 mmol, 1.0 equivalent) in concentrated H ₂ SO ₄ (20 mL) was added a solution of KNO ₃ (0.75 g, 7.4 mmol, 1.1 equivalent) in sulfuric acid (13 mL) . The reaction was stirred at 0°C for 1 hour. After completing the reaction, the mixture was poured into ice water. The white precipitate was filtered out, washed with water and dried. The solid was triturated with EtOAc, filtered and dried under vacuum to give 72.1 (1.0 g, 76.7%). MS (ES): m/z 193.16 [M+H] ⁺ .

Synthesis of compound 72.3. To a suspension of compound 72.1 (0.1g, 0.5mmol, 1.0 equivalent) in MeOH (4.0mL) and water (1.0mL) was added NH ₄ Cl (0.26g, 5.0mmol, 10 equivalents) and iron powder (0.28g, 5mmol, 10 equivalents). The reaction was stirred under reflux for 2 hours. After completing the reaction, the mixture was partitioned between water and EtOAc, and filtered through Celite. The organic layer was dried over Na ₂ SO ₄ and concentrated under reduced pressure to obtain a crude material. The crude material was purified by column chromatography to provide 72.3 (0.065g, 76.9%). MS (ES): m/z 163.18 [M+H] ⁺ .

Synthesis of compound 72.4. To a mixture of 52.1 (0.1g, 0.262mmol, 1.0 equivalent) in 1,4-dioxane (2.5mL) was added compound 72.3 (0.051g, 0.315mmol, 1.2 equivalent) and K ₂ CO ₃ (0.054g, 0.363 mmol, 1.5 equivalents). The mixture was degassed with argon for 10 minutes, then Pd ₂ (dba) ₃ (0.024 g, 0.026 mmol, 0.1 equivalent) and Xantphos (0.03 g, 0.052 mmol, 0.2 equivalent) were added, and degassed again for 5 minutes. The reaction was stirred at 100°C for 2 hours. After completing the reaction, the mixture was poured into water, and the product was extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain crude material. The crude material was purified by column chromatography to provide 72.4 (0.10 g, 77.3%). MS (ES): m/z 507.49 [M+H] ⁺ .

Synthesis of compound I-72. To a solution of 72.4 (0.103 g, 0.202 mmol, 1.0 equivalent) in CH ₂ Cl ₂ (3.0 mL) was added TFA (1.0 mL). The reaction mixture was stirred at room temperature for 1 hour. After completing the reaction, the mixture was poured into water, _{basified with saturated NaHCO 3} and extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain I-72 (0.070 g, 84.7%). MS(ES): m/z 407.38[M+H] ⁺ ; ¹ H NMR (DMSO-d ₆ , 400MHz): δ 8.89 (s, 1H), 8.67 (s, 1H), 7.67-7.66 (d, 1H) ), 7.57-7.47(m, 2H), 7.21-7.17(t, 2H), 7.11-7.08(d, 1H), 6.76(s, 1H), 4.56-4.53(t, 2H), 4.38(s, 2H) ), 2.81-2.78 (t, 2H).

Example 73. Synthesis of 2-(2,6-difluorophenyl)-4-((6-((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrole-5(3H) -Yl)pyridin-3-yl)amino)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, 1-73

Synthesis of compound 73.2. To 73.1 (0.19g, 1.336mmol, 1.0 equivalent) and (3aR, 6aS)-hexahydro-1H-furo[3,4-c]pyrrole (0.2g, 1.34mmol, 1.0 equivalent) contained in anhydrous DMSO (5.0 mL) was added DIPEA (2.37ml, 13.36mmol, 10.0 equivalent) to the stirred solution. The reaction was stirred at 110°C for 2 hours. After completing the reaction, the mixture was poured into water and extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain crude material. The crude material was purified by grinding to provide 73.2 (0.24 g, 76.3%). MS (ES): m/z 235.24 [M+H] ⁺ .

Synthesis of compound 73.3. Under nitrogen, to a suspension of 10% Pd/C (0.15 g) in MeOH (2.5 mL) was added a solution of compound 73.2 (0.24 g, 1.02 mmol, 1.0 equivalent) in MeOH (2.5 mL). The H ₂ gas was bubbled into the reaction mixture for 2 hours. After completing the reaction, the mixture was filtered through Celite and washed with MeOH. The filtrate obtained was concentrated under reduced pressure to obtain a crude material, which was subjected to column chromatography to obtain 73.3 (0.15 g, 71.6%). MS (ES): m/z 205.26 [M+H] ⁺ .

Synthesis of compound 73.4. To a mixture of 52.1 (0.1g, 0.263mmol, 1.2 equivalent) in 1,4-dioxane (3.0mL) was added compound 73.3 (0.045g, 0.219mmol, 1.0 equivalent) and K ₂ CO ₃ (0.06g, 0.438 mmol, 2.0 equivalents). The reaction was degassed with argon for 10 minutes, and then Pd ₂ (dba) ₃ (0.02 g, 0.021 mmol, 0.1 equivalent) and Xantphos (0.025 g, 0.043 mmol, 0.2 equivalent) were added. The reaction was stirred at 100°C for 2 hours. After completing the reaction, the mixture was poured into water, and the product was extracted with EtOAc. The organic layers were combined, washed with brine solution, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain 73.4 (0.1 g, 69.3%). MS (ES): m/z 549.58 [M+H] ⁺ .

Synthesis of compound I-73. To a solution of compound 73.4 (0.1 g, 0.18 mmol, 1.0 equivalent) in CH ₂ Cl ₂ (3.0 mL) was added TFA (0.4 mL). The reaction was stirred at room temperature for 1 hour. After completing the reaction, the mixture was poured into water, _{basified with saturated NaHCO 3} solution and extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain a crude material, which was purified by trituration _{with n-pentane and Et 2} O to obtain pure I-73 (0.055g, 67.3 %). MS(ES): m/z 449.46[M+H] ⁺ ; ¹ H NMR (DMSO-d ₆ , 400MHz): δ 8.61-8.59(d,1H), 8.08-8.07(d,1H), 7.53-7.46 (m,2H),7.19-7.15(t,2H),6.56-6.53(m,2H),4.36(s,2H),3.86-3.82 (m,2H),3.56-3.51(m,4H),3.33 -3.32(m,2H), 3.00(m,2H).

Example 74. Synthesis of 3-fluoro-2-(5-oxo-4-((6-((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrole-5(3H) -Yl)pyridin-3-yl)amino)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)benzonitrile, 1-74

Synthesis of compound 74.2. To a mixture of 74.1 (0.08g, 0.206mmol, 1.2 equivalent) in 1,4-dioxane (2.5mL) was added 73.3 (0.035g, 0.172mmol, 1.0 equivalent) and K ₂ CO ₃ (0.048g, 0.344mmol) , 2.0 equivalent). The reaction mixture was degassed with argon for 10 minutes, then Pd ₂ (dba) ₃ (0.016 g, 0.017 mmol, 0.1 equivalent) and Xantphos (0.02 g, 0.034 mmol, 0.2 equivalent) were added, and degassed again for 5 minutes. The reaction was stirred at 100°C for 2 hours. After completing the reaction, the mixture was poured into water, and the product was extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain 74.2 (0.075 g, 65.3%). MS (ES): m/z 556.60 [M+H] ⁺ .

Synthesis of compound I-74. To a solution of compound 74.3 (0.075 g, 0.134 mmol, 1.0 equivalent) in CH ₂ Cl ₂ (3.0 mL) was added TFA (0.4 mL). The mixture was stirred at room temperature for 1 hour. After completing the reaction, the mixture was poured into water, _{basified with saturated NaHCO 3} and extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain crude material. The crude material was purified by trituration with n-hexane and Et ₂ O to provide I-74 (0.03 g, 48.8%). MS(ES): m/z 456.48[M+H] ⁺ ; ¹ H NMR (MeOD, 400MHz): δ 8.10 (d, 1H), 7.72-7.55 (m, 4H), 6.75 (s, 1H), 6.67 -6.65(d,1H),4.48(s,2H),4.00-3.96(m,2H),3.72-3.65(m,4H),3.44-3.43(m,2H),3.15-3.12(m,2H) .

Example 75. Synthesis of 2-(4-((5-(6-azaspiro[2.5]oct-6-yl)pyridin-2-yl)amino)-5-oxo-6,7-dihydro -5H-Pyrrolo[3,4-b]pyridin-2-yl)-3-fluorobenzonitrile, I-75

Synthesis of compound 75.1. To a mixture of 74.1 (0.075g, 0.193mmol, 1.0 equivalent) in 1,4-dioxane (2.5mL) was added compound 20.3 (0.043g, 0.212mmol, 1.1 equivalent) and K ₂ CO ₃ (0.080g, 0.579 mmol, 3.0 equivalents). The mixture was degassed with argon, and then Pd ₂ (dba) ₃ (0.018 g, 0.019 mmol, 0.1 equivalent) and Xantphos (0.022 g, 0.039 mmol, 0.2 equivalent) were added, and degassed again for 5 minutes. Then, the reaction was stirred at 100°C for 0.5 hour. After completing the reaction, the mixture was poured into water and extracted with EtOAc. The organic layers were combined, washed with brine solution, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain 75.1 (0.05 g, 46.6%). MS (ES): m/z 555.6 [M+H] ⁺ .

Synthesis of compound I-75. To a solution of 75.1 (0.05 g, 0.09 mmol, 1.0 equivalent) in CH ₂ Cl ₂ (1.0 mL) was added TFA (0.2 mL). The mixture was stirred at room temperature for 1 hour. After completing the reaction, the mixture was poured into water, _{basified with saturated NaHCO 3} solution and extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain I-75 (0.04 g, 97.6%). MS(ES): m/z 455.57[M+H] ⁺ ; ¹ H NMR (CDCl ₃ , 400MHz): δ 9.41 (s, 1H), 8.65-8.64 (d, 1H), 8.07-8.06 (d, 1H) ),7.64-7.63(d,1H),7.55-7.43(m,2H),7.35-7.32(dd,1H),6.94-6.92(d,1H),6.19(s,1H),4.55(s,2H) ), 3.23-3.20 (t, 4H), 1.56-1.53 (t, 4H), 0.48 (s, 4H).

Example 76. Synthesis of 3-fluoro-2-(5-oxo-4-((5-((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrole-5(3H) -Yl)pyridin-2-yl)amino)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine -2-yl)benzonitrile, I-76

Synthesis of compound 76.1. To a mixture of 74.1 (0.1g, 0.258mmol, 1.0 equivalent) in 1,4-dioxane (3.0mL) was added 59.2 (0.052g, 0.258mmol, 1.0 equivalent) and K ₂ CO ₃ (0.089g, 0.645mmol) , 2.5 equivalents). The reaction mixture was degassed with argon for 10 minutes, then Pd ₂ (dba) ₃ (0.023 g, 0.025 mmol, 0.1 equivalent) and Xantphos (0.029 g, 0.051 mmol, 0.2 equivalent) were added, and degassed again for 5 minutes. The reaction was stirred at 100°C for 2 hours. After completing the reaction, the mixture was poured into water, and the product was extracted with EtOAc. The organic layers were combined, washed with brine solution, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain a crude material. The crude material was purified by column chromatography to obtain pure 76.1 (0.075g, 52.3%). MS (ES): m/z 556.60 [M+H] ⁺ .

Synthesis of compound I-76. Compound 76.1 (0.075 g, 0.134 mmol, 1.0 equivalent) was dissolved in CH ₂ Cl ₂ (2.0 mL), and TFA (0.3 mL) was added. The reaction was stirred at room temperature for 1 hour. After completing the reaction, the mixture was poured into water, _{basified with saturated NaHCO 3} solution, and the product was extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain crude material. The crude material was purified by column chromatography to obtain pure I-76 (0.027g, 43.9%). MS(ES): m/z 456.48[M+H] ⁺ ; ¹ H NMR (CDCl ₃ , 400MHz): δ 9.48 (s, 1H), 8.84 (s, 1H), 8.39 (s, 1H), 7.88- 7.86 (dd, 1H), 7.80-7.71 (m, 3H), 7.18-7.11 (m, 2H), 4.41 (s, 2H), 3.87-3.83 (dd, 2H), 3.53-3.50 (dd, 2H), 3.34-3.28 (m, 2H), 3.20-3.17 (dd, 2H), 2.98 (m, H).

Example 77. Synthesis of 2-(2,6-difluorophenyl)-4-((3-oxo-3H-spiro[benzofuran-2,1'-cyclopropyl]-6-yl)amino )-6,7-Dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, I-77

Synthesis 77.2. To a _{cooled solution of NaHCO 3} (1.38 g, 16.4 mmol, 1.37 equivalents) in water (15 mL) was added compound 77.1 (2.0 g, 12.0 mmol, 1.0 equivalents) in EtOAc (30 mL). The reaction was stirred for 10 minutes. Acetyl chloride (1.28 g, 16.4 mmol, 1.37 equivalents) was added to the mixture over 15 minutes, and the reaction was stirred at room temperature for 2 hours. After completing the reaction, the mixture was quenched with water and extracted with EtOAc. The organic layers were combined, washed with saturated NaHCO ₃ , dried over Na ₂ SO ₄ and concentrated under reduced pressure to obtain a crude material. The crude material was purified by trituration with EtOAc and n-hexane to provide 77.2 (2.2 g, 87.9%). MS (ES): m/z 209.20 [M+H] ⁺ .

Synthesis 77.3. To a solution of compound 77.2 (2.2g, 10.5mmol, 1.0 equivalent) in acetone (5.5mL) was added K ₂ CO ₃ (1.8g, 13.1mmol, 1.25 equivalent) and 3-bromodihydrofuran-2(3H)- Ketone (2.3 g, 14 mmol, 1.33 equivalents). The reaction was stirred at 60°C for two days. After completing the reaction, the mixture was cooled to room temperature, and the product was filtered through Celite. The celite bed was washed with acetone, and the filtrate was concentrated under reduced pressure to obtain a crude material. The crude material was purified by column chromatography to provide 77.3 (0.70 g, 22.7%). MS (ES): m/z 294.28 [M+H] ⁺ .

Synthesis 77.4. To a mixture of 77.3 (0.5 g, 1.7 mmol, 1.0 equivalent) and Ac ₂ O (7.5 mL) was added Et ₃ N (1.5 mL). The reaction was stirred for 12 hours under reflux. After completing the reaction, the mixture was quenched with water, and the product was extracted with EtOAc. The organic layers were combined, washed with saturated NaHCO ₃ and brine solution, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain a crude material. The crude material was purified by column chromatography to provide 77.4 (0.21 g, 47.2%). MS (ES): m/z 262.23 [M+H] ⁺ .

Synthesis of 77.5. To a solution of 77.4 (0.2 g, 0.76 mmol, 1.0 equivalent) in DMSO (0.5 mL) was added NaCl (0.009 g, 0.167 mmol, 0.22 equivalent). The reaction mixture was heated at 150°C for 1 hour. After completing the reaction, the mixture was quenched with water, and the product was extracted with EtOAc. The organic layers were combined, washed with saturated NaHCO ₃ and brine solution, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain a crude material. The crude material was purified by trituration with n-hexane to provide a purity of 77.5 (0.115 g, 69.2%). MS (ES): m/z 217.22 [M+H] ⁺ .

Synthesis 77.6. To a solution of 77.5 (0.1 g, 0.46 mmol, 1.0 equivalent) in MeOH (2.0 mL) was added KOH (0.077 g, 1.38 mmol, 3.0 equivalent). The reaction mixture was stirred at 65°C for 2 hours. After completing the reaction, the mixture was quenched with water, and the product was extracted with EtOAc. The organic layers were combined, washed with saturated NaHCO ₃ and brine solution, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain a crude material, which was purified by trituration with n-hexane to obtain pure 77.6 (0.074g, 91.8%) . MS (ES): m/z 175.19 [M+H] ⁺ .

Synthesis 77.7. To a mixture of 52.1 (0.085g, 0.22mmol, 1.0 equivalent) in 1,4-dioxane (2.0mL) was added compound 77.6 (0.039g, 0.22mmol, 1.0 equivalent) and K ₂ CO ₃ (0.06g, 0.44 mmol, 2.0 equivalents). The reaction mixture was degassed with argon for 10 minutes, and then Pd ₂ (dba) ₃ (0.022 g, 0.022 mmol, 0.1 equivalent) and Xantphos (0.025 g, 0.044 mmol, 0.2 equivalent) were added. Degas the suspension for another 5 minutes. The reaction was stirred at 100°C for 2 hours. After completing the reaction, the mixture was poured into water, and the product was extracted with EtOAc. The organic layers were combined, washed with brine solution, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain 77.7 (0.081 g, 69.9%). MS (ES): m/z 519.50 [M+H] ⁺ .

Synthesis of I-77. To a solution of compound 77.7 (0.081 g, 0.153 mmol, 1.0 equivalent) in CH ₂ Cl ₂ (1.0 mL) was added TFA (0.5 mL). The reaction was stirred at room temperature for 1 hour. After completing the reaction, the mixture was poured into water, _{basified with saturated NaHCO 3} solution and extracted with EtOAc. The organic layers were combined, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain crude material. The crude material was purified by trituration with n-pentane to provide I-77 (0.049 g, 75.9%). MS(ES): m/z 419.39[M+H] ⁺ ; ¹ H NMR (DMSO-d ₆ , 400MHz): δ 9.53 (s, 1H), 8.88 (s, 1H), 7.67-7.65 (d, 1H) ), 7.58-7.50 (m, 2H), 7.32 (d, 1H), 7.26-7.16 (m, 3H), 4.45 (s, 2H), 1.76-1.73 (q, 2H), 1.42-1.39 (q, 2H) ).

Example 78. Synthesis of 2-(2,6-difluorophenyl)-4-((5-(1,1,1-trifluoro-2-hydroxyprop-2-yl)pyridin-2-yl)amino )-6,7-Dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, I-78

Synthesis of compound 78.2. Compound 78.1 (1.0 g, 6.0 mmol, 1.0 equivalent) was dissolved in THF (10.0 mL) and cooled to 0°C. To the mixture were added trimethyl(trifluoromethyl)silane (1.27 g, 9.0 mmol, 1.5 equivalents) and TBAF (0.120 g, 1.2 mmol, 0.02 equivalents). The reaction was stirred at room temperature for 24 hours. After completing the reaction, the mixture was quenched with 2N HCl solution and extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain crude material. The crude material was purified by column chromatography to provide 78.2 (0.95 g, 65.5%). MS (ES): m/z 225.60 [M+H] ⁺ .

Synthesis of compound 78.3. To a solution of 78.2 (0.45g, 1.99mmol, 1.0 equivalent) in THF (5.0mL) was added (2-biphenyl) dicyclohexylphosphine (0.14g, 0.4mmol, 0.2 equivalent) and Pd ₂ (dba) ₃ ( 0.182g, 0.2mmol, 0.1 equivalent). The reaction was degassed with argon for 30 minutes. Add LHMDS (12 mmol, 6.0 equivalents) and stir the reaction at reflux temperature for 6 hours. After completing the reaction, the mixture was quenched with cold HCl solution and extracted with EtOAc. The aqueous layers were combined, _{basified with NaHCO 3} and extracted with EtOAc. The organic layer was washed with water, brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure to obtain a crude material. The crude material was purified by trituration _{with Et 2} O to obtain 78.3 (0.52 g, 99.0%). MS (ES): m/z 206.17 [M+H] ⁺ .

Synthesis of compound 78.4. To a mixture of 53.1 (0.250g, 0.65mmol, 1.0 equivalent) in 1,4-dioxane (2.5mL) was added 78.3 (0.135g, 0.65mmol, 1.0 equivalent) and K ₂ CO ₃ (0.180g, 1.3mmol) , 2.0 equivalent). The reaction mixture was degassed with argon for 10 minutes, then Pd ₂ (dba) ₃ (0.060 g, 0.065 mmol, 0.1 equivalent) and Xantphos (0.075 g, 0.13 mmol, 0.2 equivalent) were added, and degassed again for 5 minutes. The reaction was stirred at 100°C for 2 hours. After completing the reaction, the mixture was poured into water, and the product was extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain crude material. The crude material was purified by column chromatography to provide 78.4 (0.23 g, 63.6%). MS (ES): m/z 550.49 [M+H] ⁺ .

Synthesis of compound I-78. To a solution of compound 78.4 (0.21 g, 0.381 mmol, 1.0 equivalent) in CH ₂ Cl ₂ (2.0 mL) was added TFA (0.5 mL). The reaction mixture was stirred at room temperature for 1 hour. After completing the reaction, the mixture was poured into water, _{basified with saturated NaHCO 3} solution, and the product was extracted with EtOAc. The organic layers were combined, washed with brine solution, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain a crude material, which was purified by trituration to obtain I-78 (0.17 g, 98.9%). MS(ES): m/z 450.37[M+H] ⁺ ; ¹ H NMR (DMSO-d ₆ , 400MHz): δ 9.83(s, 1H), 8.93(s, 1H), 8.62(s, 1H), 8.51(d,1H),7.95-7.93(t,1H),7.60-7.56(m,1H),7.29-7.20(m,3H),6.74 (s,1H),4.45(s,2H),1.70( s,3H).

Example 79. Synthesis of 2-(4-((6-(4-oxa-7-azaspiro[2.5]oct-7-yl)pyridin-3-yl)amino)-5-oxo-6 ,7-Dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)-3-fluorobenzonitrile, I-79

Synthesis of compound 79.2. To a mixture of 79.1 (0.019g, 0.121mmol, 1.0 equivalent) in EtOAc (2.0mL) was added 4-oxa-7-azaspiro[2.5]octane (0.02g, 0.133mmol, 1.1 equivalent) and Et ₃ N (0.031 g, 0.29 mmol, 2.4 equivalents). The reaction was stirred at 80°C for 3 hours. After completing the reaction, the solvent was evaporated under reduced pressure. The residue was triturated with 0.2% dichloromethane in hexane to obtain 79.2 (0.054 g, 99.0%). MS (ES): m/z 236.27 [M+H] ⁺ .

Synthesis of compound 79.3. Under nitrogen, to a suspension of 10% Pd/C (0.030 g) in MeOH (2.0 mL) was added a solution of compound 79.2 (0.054 g, 0.229 mmol, 1.0 equivalent) in MeOH (2.0 mL). The reaction was purged with H ₂ gas for 1 hour. After completing the reaction, the mixture was filtered through Celite and washed with MeOH. The filtrate was concentrated under reduced pressure. The residue was triturated with 0.5% CH ₂ Cl ₂ in hexane to obtain pure 79.3 (0.047 g, 99.0%).

Synthesis of compound 79.4. To a mixture of 74.1 (0.075g, 0.193mmol, 1.0 equivalent) in 1,4-dioxane (3.0ml) was added 79.3 (0.044g, 0.212mmol, 1.0 equivalent) and K ₂ CO ₃ (0.08g, 0.579mmol) , 3.0 equivalents). The mixture was degassed with argon for 10 minutes, and then Pd ₂ (dba) ₃ (0.017 g, 0.019 mmol, 0.1 equivalent) and Xantphos (0.022 g, 0.038 mmol, 0.2 equivalent) were added. The reaction mixture was degassed for another 5 minutes and then stirred at 100°C for 2 hours. After completing the reaction, the mixture was poured into water, and the product was extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain crude material. The crude material was purified by column chromatography to provide 79.4 (0.05 g, 46.5%). MS (ES): m/z 557.78 [M+H] ⁺ .

Synthesis of compound I-79. To a solution of 79.4 (0.050 g, 0.089 mmol, 1.0 equivalent) in CH ₂ Cl ₂ (2.0 mL) was added TFA (0.5 mL). The reaction was stirred at room temperature for 1.5 hours. After completing the reaction, the mixture was poured into water, _{basified with saturated NaHCO 3} and extracted with EtOAc. The organic layers were combined, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain a crude material. The crude material was purified by column chromatography to provide I-79 (0.025g, 61.0%). MS(ES): m/z 457.57[M+H] ⁺ ; ¹ H NMR (CDCl ₃ , 400MHz): δ 8.42 (s, 1H), 8.22-8.21 (d, 1H), 7.60-7.58 (d, 1H) ),7.54-7.37(m,3H),6.81(s,1H),6.70-6.68(d,1H),6.18(s,1H),4.54(s,2H),3.93-3.90(t,2H), 3.67-3.64 (t, 2H), 3.51 (s, 2H), 0.86 (t, 2H), 0.56 (t, 2H).

Example 80. Synthesis of 2-(4-((3,3-dimethyl-2,3-dihydrobenzofuran-6-yl)amino)-5-oxo-6,7-dihydro- 5H-pyrrolo[3,4-b]pyridin-2-yl)-3-fluorobenzonitrile, I-80

Synthesis of compound 80.1. To a solution of 74.1 (0.1g, 0.25mmol, 1.0 equivalent) in 1,4-dioxane (2.5mL) was added 3,3-dimethyl-2,3-dihydrobenzofuran-6-amine ( 0.041 g, 0.25 mmol, 1.0 equivalent) and K ₂ CO ₃ (0.069 g, 0.5 mmol, 2.0 equivalent). After degassing with argon (10 minutes), Pd ₂ (dba) ₃ (0.022 g, 0.025 mmol, 0.1 equivalent) and Xantphos (0.029 g, 0.05 mmol, 0.2 equivalent) were added. The suspension was degassed with argon for another 5 minutes and then stirred at 100°C for 2 hours. After completing the reaction, the mixture was poured into water and extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain crude material. The crude material was purified by column chromatography to provide 80.1 (0.065g, 49.0%). MS (ES): m/z 514.56 [M+H] ⁺ .

Synthesis of compound I-80. To a solution of 80.1 (0.065 g, 0.126 mmol, 1.0 equivalent) in CH ₂ Cl ₂ (2.0 mL) was added TFA (0.5 mL). The reaction mixture was stirred at room temperature for 1 hour. After completing the reaction, the mixture was poured into ice water, _{basified with NaHCO 3} and extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain crude material. The crude material was purified by column chromatography to provide I-80 (0.026 g, 49.7%). MS(ES): m/z 414.44[M+H] ⁺ ; ¹ H NMR (DMSO-d ₆ , 400MHz): δ 8.96 (s, 1H), 8.75 (s, 1H), 7.85-7.83 (m, 1H) ), 7.72-7.70 (m, 2H), 7.22-7.17 (m, 2H), 6.88-6.62 (m, 2H), 4.40 (s, 2H), 4.24 (s, 2H), 1.29 (s, 6H).

Example 81. Synthesis of 2-(4-((2-(2-cyano-6-fluorophenyl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b] (Pyridin-4-yl)amino)phenyl)-N-ethyl-2-methylpropanamide, I-81

Synthesis of compound 81.1. To a mixture of 74.1 (0.1g, 0.258mmol, 1.0 equivalent) in 1,4-dioxane (2.5mL) was added 67.3 (0.053g, 0.258mmol, 1.0 equivalent) and K ₂ CO ₃ (0.089g, 0.645mmol) , 2.5 equivalents). After degassing with argon for 10 minutes, Pd ₂ (dba) ₃ (0.024 g, 0.0258 mmol, 0.1 equivalent) and Xantphos (0.03 g, 0.052 mmol, 0.2 equivalent) were added. The suspension was degassed for another 5 minutes and then stirred at 100°C for 2 hours. After completing the reaction, the mixture was poured into water, and the product was extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain crude material. The crude material was purified by column chromatography to provide 81.1 (0.09g, 62.6%). MS (ES): m/z 557.63 [M+H] ⁺ .

Synthesis of compound I-81. To a solution of 81.1 (0.09 g, 0.16 mmol, 1.0 equivalent) in CH ₂ Cl ₂ (3.0 mL) was added TFA (0.5 mL). The reaction was stirred at room temperature for 1 hour. After completing the reaction, the mixture was poured into ice water, _{basified with saturated NaHCO 3} and extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain crude material. The crude material was purified by column chromatography to provide I-81 (0.04g, 54.2%). MS(ES): m/z 457.51[M+H] ⁺ ; ¹ H NMR (DMSO-d ₆ ,400MHz): δ 9.04(s,1H),8.77(s,1H),7.85-7.83(m,1H ), 7.72-7.68 (m, 2H), 7.39-7.31 (m, 5H), 7.18 (s, 1H), 4.40 (s, 2H), 3.07-3.01 (m, 2H), 1.43 (s, 6H), 0.96-0.92(t,H).

Example 82. Synthesis of (S)-2-(2,6-difluorophenyl)-4-((5-(1,1,1-trifluoro-2-hydroxyprop-2-yl)pyridine-2- (Amino)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, I-82

Compound I-82 was prepared by isolating compound I.78 . MS(ES): m/z 450.37[M+H] ⁺ , ¹ H NMR (MeOD, 400MHz): δ 8.81 (s, 1H), 8.56 (d, 1H), 8.01-7.98 (m, 1H), 7.58 -7.53 (m, 1H), 7.19-7.11 (m, 3H), 4.51 (s, 2H), 1.76 (s, 3H).

Example 83. Synthesis of (R)-2-(2,6-difluorophenyl)-4-((5-(1,1,1-trifluoro-2-hydroxy-prop-2-yl)pyridine-2 -Amino)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, 1-83

Compound I-83 was prepared by isolating compound I.78 . MS(ES): m/z 450.37[M+H] ⁺ ; ¹ H NMR (MeOD, 400MHz): δ 8.80 (s, 1H), 8.56-8.55 (d, 1H), 8.00-7.98 (m, 1H) , 7.55 (m, 1H), 7.18-7.10 (m, 3H), 4.50 (s, 2H), 1.76 (s, 3H).

Example 84. Synthesis of 2-(2,6-difluorophenyl)-4-((4-(morpholin-4-carbonyl)phenyl)-amino)-5-oxo-6,7-di Hydrogen-5H-pyrrolo[3,4-b]pyridine 1-oxide, I-84

Synthesis of compound 84.1. Compound 53.1 (0.2 g, 0.53 mmol, 1.0 equivalent) and MCPBA (0.09, 0.53 mmol, 1.0 equivalent) were dissolved in CH ₂ Cl ₂ (5.0 mL). The reaction was stirred at 40°C for 4 days. After completing the reaction, the mixture was poured into water, and the product was extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain crude material. The crude material was purified by column chromatography to provide 84.1 (0.15 g, 72.0%). MS (ES): m/z 396.77 [M+H] ⁺ .

Synthesis of compound 84.2. To a suspension of compound 84.1 (0.15g, 0.38mmol, 1.0 equivalent) in 1,4-dioxane (3.0ml) was added (4-aminophenyl)(morpholinyl)methanone (0.078g, 0.378) mmol, 1.0 equivalent) and K ₂ CO ₃ (0.156 g, 1.13 mmol, 3.0 equivalent). After degassing the suspension with argon (10 minutes), Pd ₂ (dba) ₃ (0.034 g, 0.037 mmol, 0.1 equivalent) and Xantphos (0.043 g, 0.075 mmol, 0.2 equivalent) were added. The suspension was degassed for 5 minutes and heated at 100°C for 2 hours. After completing the reaction, the mixture was poured into water, and the product was extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain crude material. The crude material was purified by column chromatography to provide 84.2 (0.05 g, 23.3%). MS (ES): m/z 566.56 [M+H] ⁺ .

Synthesis of compound I-84. To a solution of 84.2 (0.05 g, 0.088 mmol, 1.0 equivalent) in CH ₂ Cl ₂ (2.0 mL) was added TFA (0.5 mL). The reaction was stirred at room temperature for 1 hour. After completing the reaction, the mixture was poured into water, _{basified with saturated NaHCO 3} and extracted with EtOAc. The organic layers were combined, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain I-84 (0.020 g, 48.6%). MS(ES): m/z 466.44[M+H] ⁺ ; ¹ H NMR (DMSO-d ₆ , 400MHz): δ 9.08(s, 1H), 9.05(s, 1H), 7.62(m, 1H), 7.46-7.37 (m, 5H), 7.27-7.23 (t, 2H), 4.50 (s, 2H), 3.58-3.38 (m, 8H).

Example 85. Synthesis of 2-(4-((3,3-dimethyl-2,3-dihydrofuro[2,3-b]pyridin-6-yl)amino)-5- pendant oxy- 6,7-Dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)-3-fluorobenzonitrile, I-85

Synthesis of compound 85.2. At -20°C, to a solution of LDA (2.1 g, 21.0 mmol, 1.05 equivalents) in THF (15.0 mL) was added n-BuLi (8.6 ml, 21.0 mmol, 1.05 equivalents). The reaction was stirred at the same temperature for 1 hour. Compound 85.1 (2.0 g, 20.0 mmol, 1.0 equivalent) was added at -78°C, and the reaction was stirred for 3 hours. Then, a solution of I ₂ (5.3 g, 21.0 mmol, 1.05 equivalent) in THF (15.0 mL) was added dropwise to the reaction mixture, and the reaction was stirred for 1 hour. After completing the reaction, the mixture was poured into water, and the product was extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain pure 85.2 (1.7 g, 37.0%). MS (ES): m/z 222.99 [M+H] ⁺ .

Synthesis of compound 85.3. 2-Methylprop-2-en-1-ol (0.32 g, 4.5 mmol, 1.0 equivalent) was added to a solution of NaH (0.2 g, 9.0 mmol, 2.0 equivalent) in THF (10.0 mL). Compound 85.2 (1.0 g, 4.5 mmol, 1.0 equivalent) was added to the mixture. The reaction was stirred at room temperature for 2 hours. After the reaction was completed, water was added to the reaction mixture, and the product was extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain pure 85.3 (0.3 g, 24.3%). MS (ES): m/z 275.09 [M+H] ⁺ .

Synthesis of compound 85.4. Mix compound 85.3 (1.0g, 3.6mmol, 1.0 equivalent), TBAC (1.0g, 3.6mmol, 1.0 equivalent), sodium formate (0.24g, 3.6mmol, 1.0 equivalent) and K ₂ CO ₃ ( 1.5 g, 10.9 mmol, 3.0 equivalents), and degas the suspension with argon for 15 minutes. Pd(OAC) ₂ (0.08 g, 0.36 mmol, 0.1 equivalent) was added to the mixture, and the reaction was stirred at 100° C. for 2 hours. After the reaction was completed, water was added, and the product was extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain crude material. The crude material was purified by column chromatography to provide 85.4 (0.3 g, 55.3%). MS (ES): m/z 149.19 [M+H] ⁺ .

Synthesis of compound 85.5. At 0°C, to a solution of 85.4 (0.23 g, 1.54 mmol, 1.0 equivalent) in CH ₂ Cl ₂ (5.0 mL) was added m-CPBA (0.39 g, 2.31 mmol, 1.5 equivalent). The reaction was stirred at room temperature for 2 hours. After completing the reaction, the mixture was poured into water, and the product was extracted _{with CH 2} Cl _2. The organic layers were combined, washed with brine solution, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain a crude material. The crude material was purified by column chromatography to provide 85.5 (0.1 g, 39.3%). MS (ES): m/z 165.19 [M+H] ⁺ .

Synthesis of compound 85.6. Compound 85.5 (0.3 g, 1.81 mmol, 1.0 equivalent) was dissolved in POCl ₃ (5.0 mL), and the reaction was stirred at 100° C. for 6 hours. After completing the reaction, _{the reaction was quenched with saturated NaHCO 3} and then extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain crude material. The crude material was purified by column chromatography to provide 85.6 (0.1 g, 30.0%). MS (ES): m/z 183.64 [M+H] ⁺ .

Synthesis of compound 85.7. To a solution of compound 85.6 (0.06g, 0.327mmol, 1.0 equivalent) in 1,4-dioxane (1ml) was added 2,4-dimethoxybenzylamine (0.082g, 0.149mmol, 1.5 equivalent) and Cs ₂ CO ₃ (0.319 g, 0.98 mmol, 3.0 equivalents). The reaction mixture was degassed with argon for 10 minutes, and then Pd ₂ (dba) ₃ (0.03g, 0.032mmol, 0.1 equivalent) and 2-dicyclohexylphosphino-2 ' -(N,N-dimethylamine) were added Yl)biphenyl (0.025 g, 0.065 mmol, 0.2 equivalents). The reaction was then stirred at 100°C for 2 hours. After completing the reaction, the mixture was poured into water, and the product was extracted with EtOAc. The organic layers were combined, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain crude material. The crude material was purified by column chromatography to provide 85.7 (0.04g, 43.4%). MS (ES): m/z 282.39 [M+H] ⁺ .

Synthesis of compound 85.8. Compound 85.7 (0.03 g, 0.106 mmol, 1.0 equivalent) was dissolved in TFA (1.0 mL). The reaction was stirred at 60°C for 2 hours. After completing the reaction, _{the mixture was quenched with saturated NaHCO 3} solution, and the product was extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain pure 85.8 (0.020 g, 99.0%). MS (ES): m/z 164.21 [M+H] ⁺ .

Synthesis of compound 85.9. To a mixture of 74.1 (0.047g, 0.12mmol, 1.0 equivalent) in 1,4-dioxane (3.0ml) was added compound 85.8 (0.020g, 0.12mmol, 1.0 equivalent) and K ₂ CO ₃ (0.05g, 0.36 mmol, 3.0 equivalents). The reaction mixture was degassed with argon for 10 minutes, then Pd ₂ (dba) ₃ (0.011 g, 0.012 mmol, 0.1 equivalent) and Xantphos (0.013 g, 0.024 mmol, 0.2 equivalent) were added, and degassed again for 5 minutes. The reaction was stirred at 100°C for 2 hours. After completing the reaction, the mixture was poured into water, and the product was extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain crude material. The crude material was purified by column chromatography to provide 85.9 (0.04g, 64.0%). MS (ES): m/z 515.55 [M+H] ⁺ .

Synthesis of compound I-85. To a solution of 85.9 (0.04 g, 0.077 mmol, 1.0 equivalent) in CH ₂ Cl ₂ (1.0 mL) was added TFA (1.0 mL). The reaction was stirred at room temperature for 1 hour. After completing the reaction, the mixture was poured into water, _{basified with saturated NaHCO 3} and the product was extracted with EtOAc. The organic layers were combined, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain crude material. The crude material was purified by column chromatography to provide I-85 (0.02 g, 62.1%). MS(ES): m/z 415.43[M+H] ⁺ ; ¹ H NMR (DMSO-d ₆ , 400MHz): δ 9.40 (s, 1H), 9.01 (s, 1H), 7.93-7.87 (m, 2H ), 7.77-7.72 (m, 2H), 7.58 (s, 1H), 7.18-7.16 (d, 1H), 4.49 (s, 2H), 4.25 (s, 2H), 1.49 (s, 6H).

Example 86. Synthesis of 2-(2,6-Difluorophenyl)-4-((2,2-Dioxy-1,3-dihydro-benzo[c]thiophen-5-yl)amino )-6,7-Dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, I-86

Synthesis of compound 86.2. To a solution of 86.1 (1.6g, 6.06mmol, 1.0 equivalent) in benzene (8.0mL) was added a solution of sodium sulfide monohydrate (2.9g, 12.1mmol, 2.0 equivalent) in water (30mL) and benzyl triethyl Base ammonium chloride (catalysis). The reaction was stirred at 20°C for 30 hours. After completing the reaction, the mixture was poured into water and extracted with CH ₂ Cl ₂ . The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to give 86.2 (0.7 g, 84.7%). The crude product can be used in the next step without any further purification.

Synthesis of compound 86.3. At 5 to 10°C, AcOH (4.3 mL) was added to 86.2 (0.7 g, 5.14 mmol, 1.0 equivalent). The solution was stirred for 1 hour. To this solution was added 30% H ₂ O ₂ solution (1.2 mL). The reaction mixture was stirred at 90 to 95°C for 3 hours. After completing the reaction, the mixture was poured into water, and the product was extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain crude material. The crude material was purified by column chromatography to provide 86.3 (0.3g, 34.7%). ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.40-7.28 (m, 4H), 4.4 (s, 4H).

Synthesis of compound 86.4. At 0°C, _{HNO 3} (1.0 mL) was slowly added to a solution of 86.3 (0.2 g, 1.19 mmol, 1.0 equivalent) in concentrated H ₂ SO _{4 (2.0 mL).} The reaction was stirred at 0°C for 30 minutes. After completing the reaction, the mixture was transferred to crushed ice, and the product was extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain crude material. The crude material was purified by column chromatography to provide 86.4 (0.12 g, 47.3%). ¹ H NMR (CDCl ₃ , 400 MHz): δ 8.3-8.26 (m, 2H), 7.58-7.54 (d, 1H), 4.51-4.48 (d, 4H).

Synthesis of compound 86.5. To a suspension of 10% Pd/C (0.03 g) in MeOH (3.0 mL) was added compound 86.4 (0.12 g, 0.56 mmol, 1.0 equivalent). The suspension was purged with H ₂ gas for 1 hour. The reaction mixture was filtered through Celite and concentrated under reduced pressure to obtain 86.5 (0.08 g, 77.5%). MS (ES): m/z 184.1 [M+H] ⁺ .

Synthesis of compound 86.6. To a mixture of 74.1 (0.080g, 0.21mmol, 1.0 equivalent) in 1,4-dioxane (3.0mL) was added 86.5 (0.046g, 0.21mmol, 1.0 equivalent) and K ₂ CO ₃ (0.073g, 0.53mmol) , 2.5 equivalents). The reaction mixture was degassed with argon for 10 minutes, then Pd ₂ (dba) ₃ (0.019 g, 0.021 mmol, 0.1 equivalent) and Xantphos (0.024 g, 0.042 mmol, 0.2 equivalent) were added, and degassed again for 5 minutes. The reaction was stirred at 120°C for 2 hours. After completing the reaction, the mixture was transferred to water, and the product was extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain crude material. The crude material was purified by column chromatography to provide 86.6 (0.08g, 72.2%). MS (ES): m/z 528.6 [M+H] ⁺ .

Synthesis of compound I-86. Compound 86.6 (0.08 g, 0.151 mmol, 1.0 equivalent) was dissolved in CH ₂ Cl ₂ (1.0 mL), and TFA (0.5 mL) was added to the reaction mixture. The reaction was stirred at room temperature for 1 hour. After completing the reaction, the mixture was poured into water, _{basified with saturated NaHCO 3} and the product was extracted with EtOAc. The organic layers were combined, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain crude material. The crude material was purified by column chromatography to provide I-86 (0.05 g, 77.1%). MS(ES): m/z 428.57[M+H] ⁺ ; ¹ H NMR (DMSO-d ₆ , 400MHz): δ 9.10(s, 1H), 8.75(s, 1H), 7.55-7.51(m, 1H ), 7.43-7.34 (m, 2H), 7.22-7.18 (m, 2H), 7.08 (s, 1H), 5.76 (s, 1H), 4.57-4.46 (d, 4H), 4.37 (s, 2H).

Example 87. Synthesis of 3-fluoro-2-(4-((5-(4-hydroxy-9-azabisspiro[2.1.25.33]dec-9-yl)pyridin-2-yl)amino)-5 -Pendant oxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)benzonitrile, I-87

Synthesis of compound 87.2. Iodomethane (46.2 g, 45.2 mmol, 1.0 equivalent) was added to 87.1 (5.0 g, 325 mmol, 1.1 equivalent). The reaction mixture was stirred at room temperature for 48 hours. After the reaction was completed, the solid was filtered and washed with Et ₂ O to obtain pure 87.2 (5.2 g, 91.6%). ¹ H NMR (DMSO-d ₆ , 400 MHz): δ 4.15-4.12 (t, 2H), 3.80-3.77 (t, 2H), 2.97 (s, 6H).

Synthesis of compound 87.4. The KOBu ^t (0.675g, 6.03mmol, 1.0 eq) was added to tert-butanol (10 mL) and heated to 60 ℃. To this solution was added 87.3 (1.2 g, 6.03 mmol, 1.0 equivalent) and stirred at room temperature for 1 hour. To this mixture was added 87.2 (1.36 g, 5.4 mmol, 0.9 equivalent) in portions, and the resulting mixture was stirred at room temperature for 2 hours. To this mixture was added a solution of KOBu ^t (0.68 g, 6.03 mmol, 1.0 equivalent) in tert-butanol (10 mL), and the reaction was stirred at room temperature for 48 hours. After completing the reaction, the mixture was poured into water, and the product was extracted with EtOAc. The organic layers were combined, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain crude material. The crude material was purified by column chromatography to provide 87.4 (0.2g, 13.2%). ¹ H NMR (CDCl ₃ , 400 MHz): δ 3.76 (s, 4H), 1.49 (s, 9H), 1.3-1.26 (m, 4H), 0.87 (bs, 4H).

Synthesis of compound 87.5. At 0°C, to a solution of 87.5 (0.2 g, 0.79 mmol, 1.0 equivalent) in CH ₂ Cl ₂ (5.0 mL) was added TFA (0.9 g, 7.96 mmol, 10 equivalents). The reaction was stirred for 2 hours. After completing the reaction, the solvent was concentrated under reduced pressure and _{neutralized with saturated NaHCO 3} solution. The mixture was extracted with CH ₂ Cl ₂ and the organic layers were combined, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain 87.5 (0.11 g, 91.4%). ¹ H NMR (CDCl ₃ , 400 MHz): δ 3.12 (s, 4H), 1.34-1.31 (m, 4H), 0.75-0.73 (m, 4H).

Synthesis of compound 87.6. To a solution of 87.5 (0.11g, 0.728mmol, 1.0 equivalent) in DMSO (5.0mL) was added 5-fluoro-2-nitropyridine (0.103g, 0.728mmol, 1.0 equivalent) and DIPEA (0.94g, 7.28mmol) , 10 equivalents). The reaction mixture was stirred at 100°C for 2 hours. After completing the reaction, the mixture was transferred to water and extracted with EtOAc. The organic layers were combined, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain 87.6 (0.1 g, 50.3%). MS (ES): m/z 274.3 [M+H] ⁺ .

Synthesis of compound 87.7. At 0°C, to a solution of 87.6 (0.1 g, 0.366 mmol, 1.0 equivalent) in MeOH (3.0 mL) was added NaBH ₄ (0.070 g, 1.83 mmol, 5.0 equivalent). The reaction mixture was stirred at room temperature for 1 hour. After completion, _{the reaction was quenched with saturated NH 4} Cl solution and extracted with CH ₂ Cl ₂ . The organic layers were combined, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain a crude material, which was purified by trituration with n-hexane to obtain 87.7 (0.075 g, 79.0%). MS (ES): m/z 276.38 [M+H] ⁺ .

Synthesis of compound 87.8. To a suspension of 10% Pd/C (0.05 g) in MeOH (3.0 mL) was added compound 87.7 (0.075 g, 0.272 mmol, 1.0 equivalent) and _{purged with H 2} gas for 2 hours. The reaction mixture was filtered through Celite and concentrated under reduced pressure to obtain 87.8 (0.06 g, 89.8%). MS (ES): m/z 246.37 [M+H] ⁺ .

Synthesis of compound 87.9. To a solution of 74.1 (0.090g, 0.232mmol, 1.0 equivalent) in 1,4-dioxane (2.0ml) was added 87.8 (0.051g, 0.208mmol, 1.0 equivalent) and K ₂ CO ₃ (0.080g, 0.58mmol) , 2.5 equivalents). The reaction mixture was degassed with argon for 10 minutes, then Pd ₂ (dba) ₃ (0.021 g, 0.023 mmol, 0.1 equivalent) and Xantphos (0.026 g, 0.046 mmol, 0.2 equivalent) were added, and degassed again for 5 minutes. The reaction was stirred at 110°C for 2 hours. After completing the reaction, the mixture was poured into water, and the product was extracted with EtOAc. The organic layers were combined, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain crude material. The crude material was purified by column chromatography to provide 87.9 (0.07g, 55.5%). MS (ES): m/z 597.6 [M+H] ⁺ .

Synthesis of compound I-87. Compound 87.9 (0.070 g, 0.117 mmol, 1.0 equivalent) was dissolved in CH ₂ Cl ₂ (2.0 mL), and TFA (0.5 mL) was added to the reaction mixture. The reaction was stirred at room temperature for 1 hour. After completing the reaction, the mixture was poured into water, _{basified with saturated NaHCO 3} solution and extracted with EtOAc. The organic layers were combined, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain a crude material. The crude material was purified by column chromatography to obtain I-87 (0.030 g, 51.3%). MS(ES): m/z 497.7[M+H] ⁺ ; ¹ H NMR (DMSO-d ₆ , 400MHz): δ 9.52(s, 1H), 8.86(s, 1H), 8.47(s, 1H), 7.96(d,1H),7.89-7.86(dd,1H),7.8-7.72(m,2H),7.41-7.38(dd,1H),7.09-7.07(d,1H), 4.63(d,1H), 4.42 (s, 2H), 3.23-3.20 (d, 2H), 2.79-2.76 (d, 2H), 0.46 (s, 6H), 0.34-0.32 (d, 2H).

Example 88. Synthesis of 3-fluoro-2-(4-((5-((3R,5R)-3-hydroxy-1-oxa-7-azaspiro[4.4]non-7-yl)pyridine-2 -Amino)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-2- 基)Benzonitrile. I-88

Synthesis of compound 88.2. To a stirred mixture of 88.1 (4.0g, 21.5mmol, 1.0 equivalent) and 3-bromoprop-1-ene (4.7ml, 53.9mmol, 2.5 equivalent) in THF (10.0mL) was added saturated NH ₄ Cl solution (20.0 mL). Zinc powder (2.8 g, 43.1 mmol, 2.0 equivalents) was slowly added to the suspension while maintaining the temperature below 40°C. The reaction mixture was stirred at room temperature for 12 hours. After the reaction was completed, a 10% H ₂ SO ₄ aqueous solution was slowly added. The reaction mixture was filtered, and the product was extracted with EtOAc. The organic layer was separated, washed with brine solution, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain 88.2 (4.3 g, 87.6%). ¹ H NMR (DMSO-d ₆ , 400MHz): δ 5.91-5.83 (m, 1H), 5.24-5.19 (m, 2H), 3.55-3.48 (m, H), 3.41-3.25 (m, 2H), 2.42 -2.40 (d, 2H), 1.89-1.85 (t, 2H), 1.47 (s, 9H).

Synthesis of compound 88.3. At 50°C, to a stirred mixture of 88.2 (4.3g, 18.9mmol, 1.0 equivalent) and NaIO ₄ (4.0g, 18.9mmol, 1.0 equivalent) in tert-butanol (28mL) and water (9.4mL) were added A solution of sodium metabisulfite (3.59 g, 18.9 mmol, 1.0 equivalent) in water (15.0 mL). The reaction mixture was stirred at 50°C for 12 hours and then at room temperature for 10 hours. After completing the reaction, the reaction mixture was cooled to room temperature and extracted with EtOAc. The organic layers were combined, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain 88.3 (1.0 g, 21.7%). MS (ES): m/z 244.3 [M+H] ⁺ .

Synthesis of compound 88.4. To a stirred solution of 88.3 (0.38 g, 1.56 mmol, 1.0 equivalent) in CH ₂ Cl ₂ (5.0 mL) was added TFA (1.0 mL), and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain a crude substance 88.4 (0.3 g, 80.0%), MS (ES): m/z 144.17 [M+H] ⁺ .

Synthesis of compound 88.5. To a stirred mixture of 88.4 (0.12g, 0.84mmol, 1.2 equivalent) and 5-fluoro-2-nitropyridine (0.1g, 0.70mmol, 1.0 equivalent) in DMSO (2.0mL) was added DIPEA (0.92g, 7.03 mmol, 10.0 equivalent) and heated at 90°C for 5 hours. The reaction mixture was cooled to room temperature, poured into water, and extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography to obtain 88.5 (0.125 g, 64.3%). MS (ES): m/z 266.33 [M+H] ⁺ .

Synthesis of compound 88.6. To a suspension of 10% Pd/C (0.05 g) in MeOH (5.0 mL) was added compound 88.5 (0.125 g, 0.471 mmol, 1.0 equivalent). The suspension was purged with H ₂ gas for 1 hour. The reaction mixture was filtered through Celite and concentrated under reduced pressure to obtain 88.6 (0.10 g, 94.0%). MS (ES): m/z 236.37 [M+H] ⁺ .

Synthesis of compound 88.7. To a mixture of 74.1 (0.075g, 0.193mmol, 1.0 equivalent) in 1,4-dioxane (2.0mL) was added 88.5 (0.049g, 0.212mmol, 1.1 equivalent) and K ₂ CO ₃ (0.079g, 0.579mmol) , 3.0 equivalents). The reaction mixture was degassed with argon for 10 minutes, then Pd ₂ (dba) ₃ (0.017 g, 0.019 mmol, 0.1 equivalent) and Xantphos (0.022 g, 0.038 mmol, 0.2 equivalent) were added, and degassed again for 5 minutes. The reaction was stirred at 100°C for 2 hours. After completing the reaction, the mixture was poured into water, and the product was extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain crude material. This crude material was purified by column chromatography to provide 88.7 (0.058 g, 23.3%). MS (ES): m/z 587.58 [M+H] ⁺ .

Synthesis of compound 88.8. Use reverse phase column (X-BRIDGE C18 250 x 19mm, 5μ) to separate the diastereomeric mixture 88.7 (0.058g) to obtain pure 88.8 (0.023g), MS(ES): 587.3[M+H] ⁺ .

Synthesis of compound I-88. Compound 88.8 (0.023 g, 0.039 mmol, 1.0 equivalent) was dissolved in CH ₂ Cl ₂ (2.0 mL), and TFA (0.2 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. After completing the reaction, the mixture was poured into water, _{basified with saturated NaHCO 3} , and the mixture was extracted _{with CH 2} Cl _2. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to obtain a crude material, which was purified by trituration with n-pentane to obtain pure I-88 (0.010 g, 52.4%). MS(ES): m/z 487.2[M+H] ⁺ ; ¹ H NMR (DMSO-d ₆ , 400MHz): δ 9.42(s, 1H), 8.81(s, 1H), 8.31(s, 1H), 7.88-7.85(m,1H),7.79-7.69(m,H),7.65-7.64(d,1H),7.11-7.09(d,1H),7.01-6.98(dd,1H), 4.96(d,1H) ), 4.40(s, 2H), 4.35(s, 1H), 3.83-3.79(m, 1H), 3.60-3.57(dd, 1H), 3.29(s, 1H), 3.25(s, H), 2.20- 2.13 (m, 2H), 2.08-2.00 (m, 1H), 1.88-1.84 (dd, 1H).

Example 89. Synthesis of 3-fluoro-2-(4-((5-((3S,5R)-3-hydroxy-1-oxa-7-azaspiro[4.4]non-7-yl)pyridine-2 -Amino)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)benzonitrile, 1-89

Using the procedure described in Example 89, was prepared from compound 88.7 I-89. MS(ES): m/z 487.2[M+H] ⁺ ; ¹ H NMR (DMSO-d ₆ , 400MHz): δ 9.43(s, 1H), 8.81(s, 1H), 8.31(s, 1H), 7.87-7.85(m,1H),7.78-7.70(m,2H),7.64(d,1H),7.11-7.09(d,1H),7.01-6.98(dd,1H), 4.97(d,1H), 4.40(s, 2H), 4.35(s, 1H), 3.86-3.82(m, 1H), 3.59-3.56(dd, 1H), 3.38(s, 1H), 3.26(s, 2H), 2.12-2.08( m, 1H), 2.01-1.98 (m, 2H), 1.94-1.90 (dd, 1H).

Example 90. Synthesis of 3-fluoro-2-(4-((5-((3R,5R)-3-hydroxy-1-oxa-7-azaspiro[4.4]non-7-yl)pyridine-2 -Amino)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)benzonitrile, 1-90

Compound I-89 was prepared by isolating compound I-88 . MS(ES): m/z 487.2[M+H] ⁺ ; ¹ H NMR (DMSO-d ₆ , 400MHz): δ 9.43(s, 1H), 8.82(s, 1H), 8.32(s, 1H), 7.88-7.86(dd,1H),7.79-7.71(m,H),7.65(d,1H),7.12-7.09(d,1H),7.02-6.99(dd,1H), 4.96(d,1H), 4.41(s, 2H), 4.35(s, 1H), 3.83-3.79(m, 1H), 3.60-3.58(dd, 1H), 3.29(s, 1H), 3.25(s, 2H), 2.18-2.12( m, 2H), 2.09-2.03 (m, 1H), 1.89-1.85 (dd, 1H).

Example 91. Synthesis of 3-fluoro-2-(4-((5-((3S,5S)-3-hydroxy-1-oxa-7-azaspiro[4.4] (Non-7-yl)pyridin-2-yl)amino)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)benzonitrile, I-91

Compound I-88 by chiral separation performed to obtain compound I-91. MS(ES): m/z 487.2[M+H] ⁺ ; ¹ H NMR (DMSO-d ₆ , 400MHz): 9.42(s, 1H), 8.82(s, 1H), 8.32(s, 1H), 7.88 -7.86(dd,1H),7.79-7.71(m,2H),7.65(d,1H),7.11-7.09(d,1H),7.01-6.98(dd,1H),4.98(s,1H), 4.41 (s, 2H), 4.35 (s, 1H), 3.83-3.80 (m, 1H), 3.61-3.58 (dd, 1H), 3.29 (s, 1H), 3.25 (s, 2H), 2.18-2.12 (m , 2H), 2.09-2.03 (m, 1H), 1.89-1.85 (dd, 1H).

Example 92. Synthesis of 3-fluoro-2-(4-((5-((3R,5S)-3-hydroxy-1-oxa-7-azaspiro[4.4]non-7-yl)pyridine-2 -Amino)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)benzonitrile, 1-92

Compound I-89 by chiral separation performed to obtain compound I-92. MS(ES): m/z 487.1[M+H] ⁺ ; ¹ H NMR (DMSO-d ₆ , 400MHz): δ 9.43(s, 1H), 8.81(s, 1H), 8.32(s, 1H), 7.88-7.86(dd,1H),7.77-7.71(m,2H),7.65-7.64(d,1H),7.11-7.09(d,1H),7.01-6.98(dd,1H),4.98-4.97(d ,1H),4.41(s,2H),4.35(s,1H),3.86-3.82(m,1H),3.59-3.56(dd,1H),3.30(s,2H), 3.25(s,2H), 2.13-2.08 (m, 1H), 2.02-1.99 (m, 2H), 1.94-1.90 (dd, 1H).

Example 93. Synthesis of 3-fluoro-2-(4-((5-((3S,5R)-3-hydroxy-1-oxa-7-azaspiro[4.4]non-7-yl)pyridine-2 -Amino)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)benzonitrile, 1-93

Carried by the compound I-93 manufactured by chiral separation of the compound I-89. MS(ES): m/z 487.2[M+H] ⁺ ; ¹ H NMR (DMSO-d ₆ , 400MHz): δ 9.43(s, 1H), 8.81(s, 1H), 8.32(s, 1H), 7.87-7.85(d,1H),7.77-7.71(m,2H),7.65-7.64(d,1H),7.11-7.09(d,1H),7.01-6.98(dd,1H),4.97(s,1H) ), 4.41(s, 2H), 4.36(s, 1H), 3.86-3.83(m, 1H), 3.59-3.57(dd, 1H), 3.29(s, 1H), 3.26(s, 2H), 2.13 2.08 (m, 1H), 2.02-2.00 (m, 2H), 1.94-1.91 (dd, 1H).

Example 94: Tyk2 and JAK2 radioactive kinase analysis

In reaction buffer _{(20mM Hepes pH 7.5,10mM MgCl 2,} 1mM EGTA, 0.02% Brij35,0.02mg / mL BSA, 0.1mM Na 3 PO 4, 2mM DTT, 1% DMSO) peptides were prepared by mass [KKSRGDYMTMQIG] ( 20μM). Add TYK2 (Invitrogen) kinase followed by the compound in DMSO. Add ³³ P ATP to start the reaction in 10 μM ATP. Incubate the kinase reaction at room temperature for 120 minutes, and place the reaction spot on P81 ion exchange paper (Whatman # 3698-915), then wash thoroughly in 0.75% phosphoric acid, and then read the radioactivity counter. For JAK2 (Invitrogen) kinase analysis, the peptide substrate poly[Glu: Tyr] (4:1) (0.2 mg/ml) was used in the reaction performed in the same manner as TYK2.

Example 95: Analysis of Tyk2 and JAK2 Diameter Gauges

The caliper machine uses off-chip migration variation analysis to detect the phosphorylated peptide substrate of kinase analysis, which uses microfluidic technology. These analyses were performed at an ATP concentration equal to ATP Km and 1 mM ATP. Compounds were serially diluted in DMSO and then further diluted in assay buffer (25mM HEPES, pH 7.5, 0.01% Brij-35, 0.01% Triton, 0.5mM EGTA). 5ul diluted compound first added to the wells, then add 10ul enzyme mixture to the wells, followed by addition of 10uL by mass mixture (peptide and ATP, contained in 10mM MgCl ₂₎ to initiate the reaction. Incubate the reaction at 28°C for 25 minutes, then add 25ul of stop buffer (100mM HEPES, 0.015% Brij-35, 50mM EDTA), and then read with a caliper. The final concentration of 1nM JAK2 and 9.75nM TYK2 were from Carna, and the substrate used was 20 and 16uM ATP, respectively. JAK2 analysis uses peptide 22, and TYK2 uses peptide 30 (caliper gauge), each of which is 3uM.

0.01μM；活性指定為「B」之化合物提供0.01至0.1μM之Ki；活性指定為「C」之化合物提供0.1至1.0μM之Ki；且活性指定為「D」之化合物提供Ki

1.0μM。 Table 2 shows the activity of selected compounds of the present invention in the Tyk2 and JAK2 activity inhibition assay. The compound number corresponds to the compound number in Table 1 . Compounds with activity designated as "A" provide Ki

0.01μM; the compound designated as "B" provides Ki from 0.01 to 0.1μM; the compound designated as "C" provides Ki from 0.1 to 1.0μM; and the compound designated as "D" provides Ki

1.0μM.

IL-12 induces pSTAT4 in human PBMC. Isolate human PBMC from the white blood cell layer and store frozen as needed for analysis. Thaw the cells for analysis and resuspend them in complete medium containing serum, and then dilute the cells to 1.67 E6 cells/ml, making 120 μl/well 200,000 cells. Add 15 μl of compound or DMSO to the wells at the desired concentration and incubate at 37°C for 1 hour. Add 15 μl of stimulant (IL-12 at a final concentration of 1.7 ng/mL) for 30 minutes, and then perform pSTAT4 and total STAT4 analysis, using the prepared cell lysate, and analyze by MSD reagent according to the manufacturer's protocol. The final DMSO concentration of the compound in this analysis was 0.1%.

GM-CSF induces pSTAT5 in human PBMC. Generally prepare cells for analysis as in the above procedure, and add 15μl GM-CSF (final concentration 5ng/mL) for 20 minutes, then perform pSTAT5 and total STAT5 analysis, which uses the prepared cell lysate, and according to the manufacturer’s protocol Analyze by MSD reagent. The final DMSO concentration of the compound in this analysis was 0.1%.

2μM；活性指定為「B」之化合物提供2至20μM之EC₅₀；且活性指定為「C」之化合物提供EC₅₀>20μM。 Table 3 shows the activity of the selected compounds of the present invention in the inhibition assay of IL-12-induced pSTAT4 and GM-CSF-induced pSTAT5 in human PBMC. The compound number corresponds to the compound number in Table 1. Compounds with activity designated as "A" provide EC ₅₀

2μM; the compound designated as "B" provides an EC _{50 of} 2 to 20 μM; and the compound designated as "C" provides an EC ₅₀ >20 μM.

Aimed at the acute mouse model of IL-12/IL-18 induced IFNγ in serum . C57BL/6 mice were given various doses of test compound or vehicle (n=9 or 10/group) to PO or SC, and then 30 minutes later, 10 ng IL-12 and 1 μg IL-18 were injected IP. Three hours after the injection of IL-12/IL-18, the blood of the mice was obtained and the serum was separated. CBA analysis was used to determine the concentration of cytokines in serum.

Certain compounds of the present invention inhibit about 50% of the in vivo production of IFNγ induced by IL-12/IL-18.

In vitro study of murine IL-12 inducing IFNγ. C57/BL6 mice were administered a single oral dose of vehicle or different doses of compounds, with a volume of 10 mL/kg. After 30 minutes to 1 hour of administration, the animals were euthanized, and the blood was collected in the sodium heparin blood collection tube via the vena cava and inverted several times. The blood was then inoculated on an anti-CD3 coated plate, and in a _{humidified incubator with 5% CO 2} at 37° C., and stimulated with 2ng/ml mouse IL-12 in RPMI medium for 24 hours. At the end of the incubation, the blood was centrifuged at 260 g for 5 minutes, and the supernatant was collected. According to the manufacturer's instructions (Meso Scale Discovery), the mouse IFNγ MSD kit was used to determine the IFNγ concentration in the supernatant. When collecting blood, collect plasma for the analysis of drug levels by LC-MS/MS.

Certain compounds of the invention inhibit IL-12-induced IFNγ production in an in vitro mouse model.

T-ALL cell proliferation analysis T-ALL cell lines KOPT-K1, HPB-ALL, DND-41, PEER and CCRF- are grown in RPMI-1640 medium with 10% fetal bovine serum and penicillin/streptomycin CEM. Cells were seeded in 96-well plates at 1 x 10 ^{4 cells/well in triplicate.} The T-ALL cell lines DU.528, LOUCY and SUP-T13 were cultured in the same medium and seeded at a density of ^{1.5 x 10 4 cells/well.} The cells were treated with DMSO or various compounds of the invention at different concentrations. CellTiter-Glo luminescent cell viability analysis (Promega) was used to evaluate cell viability after 72 hours of exposure to the drug. Add CellTiter-Glo reagent to the wells and incubate for 10 minutes. The luminescence was then measured with a 96-well plate luminescence reader. The DMSO-treated sample was used as 100% to calculate the cell survival rate. By non-linear regression, the IC ₅₀ value was calculated with GraphPad Prism software.

Although we have described many embodiments of the present invention, it is obvious that our basic examples can be modified to provide other embodiments using the compounds and methods of the present invention. Therefore, it should be understood that the scope of the present invention is intended to be defined by the scope of the attached patent application, rather than by the specific embodiments that have been shown by way of examples.

Claims (33)

A compound of formula I :

Or a pharmaceutically acceptable salt thereof, wherein: X and Y are each independently =C(R ⁶ )-, =N- or =N ⁺ (→O ^- )-, and the restriction is that X and Y are not at the same time = C(R ⁶ )-; Ring A is a phenyl group or a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; examples in ^{which ring A has m R 7} Substitution; R ¹ and R ^1'are each hydrogen; each R ^{2 is} independently a group selected from: C _1-6 aliphatic, phenyl, having 1 to 2 independently selected from nitrogen, oxygen and sulfur A 4- to 7-membered saturated or partially unsaturated heterocyclic ring with heteroatoms, and a 5- to 6-membered heteroaryl ring with 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; R ³ is selected from The group: phenyl, 5- to 6-membered saturated or partially unsaturated heterocyclic ring with 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 1 to 4 independently selected from nitrogen, oxygen And sulfur heteroatoms of 5 to 6 membered heteroaryl ring; wherein R ³ is substituted by n ^{instances of R 8} ; R ⁴ is hydrogen or C _1-6 aliphatic; R ^5'is one having 1 to 2 independently selected from 8-10 saturated or partially unsaturated heterocyclic ring nitrogen, oxygen and sulfur heteroatoms of the atoms; wherein R ^{5 'is} substituted with R ⁹ examples of p; ^{R. 6} is ^{hydrogen; R 7, R 8, R} 10 and R Each instance of ^{11 is independently -R 2} , halogen, -CN, -OR, -NR ₂ , -C(O)OR or -C(O)NR ₂ ; ^{each instance of R 9} is independently pendant oxy, -OH, C _1-6 hydroxy aliphatic or -R ² ; L ¹ is a covalent bond or a C _1-6 divalent saturated or unsaturated straight or branched hydrocarbon chain, wherein one or two of the chain is methylene The base unit optionally and independently undergoes -C(R ¹⁰ ) ₂ -, -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -O-, -C(O)-, -OC(O)- or -C(O)O- substitution; or L ¹ and an ^{example of R 7} together with the intervening atom are formed with 1 to 4 independently selected from nitrogen, oxygen, and sulfur and 5-10 portions boron hetero atoms of an unsaturated or aromatic ring; wherein the ring is substituted with q R & substituted ¹¹ example; and R ^{5 'is} attached to the anywhere rings formed of L ¹ and R ^7; m N is 0 to 4; p is 0 to 6; q is 0 to 4; and each R is independently hydrogen or a group selected from: C _1-6 aliphatic, phenyl, having 1 Up to 2 saturated or partially unsaturated heterocyclic rings with 4 to 7 members independently selected from nitrogen, oxygen and sulfur, and 5 to 6 with 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur Member heteroaryl ring; or two Rs on the same nitrogen and their inserted atoms together form 4 to 7 members with 0 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur in addition to the nitrogen, saturated, partially unsaturated Or heteroaryl ring. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein ring A is phenyl, pyridin-2-yl, pyridin-3-yl or pyrazol-4-yl. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein ring A is pyridin-2-yl. The compound of any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein X is =C(R ⁶ )-; and Y is =N-. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R ⁶ is hydrogen. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein L ¹ is -CH ₂ C(O)-, -C(O)- or a covalent bond. The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein L ¹ is -C(O)-. The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein L ¹ is a covalent bond. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein R ³ is phenyl, pyrrolidinyl or piperidinyl. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein R ³ is a phenyl group. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein n is 2, and at least one R ⁸ is fluorine. A compound selected from the following or a pharmaceutically acceptable salt thereof:

A pharmaceutical composition comprising a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, adjuvant or vehicle. An in vitro method for inhibiting TYK2 in a biological sample, which comprises contacting the sample with a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof. A use of the compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a disease, disease or condition mediated by TYK2 in a patient. The use according to claim 15, wherein the condition is selected from autoimmune diseases, inflammatory diseases, proliferative diseases, endocrine diseases, neurological diseases or transplant-related diseases. Such as the use of claim 16, wherein the disease is an autoimmune disease. The use of claim 17, wherein the autoimmune disease is selected from type 1 diabetes, systemic lupus erythematosus, multiple sclerosis, systemic sclerosis, psoriasis, Crohn's disease, ulcerative colon Inflammation and inflammatory bowel disease. Such as the use of claim 16, wherein the disease is an inflammatory disease. The use of claim 19, wherein the inflammatory disease is selected from rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis, Crohn's disease, ulcerative colitis and inflammatory bowel disease. Such as the use of claim 16, wherein the disease is a proliferative disease. Such as the use of claim 21, wherein the proliferative disease is hematological cancer. Such as the use of claim 21, wherein the proliferative disease is leukemia. Such as the use of claim 23, wherein the leukemia is T cell leukemia. Such as the use of claim 24, wherein the T-cell leukemia is T-cell acute lymphoblastic leukemia (T-ALL). The use of claim 21, wherein the proliferative disease is associated with one or more activating mutations of TYK2. Such as the use of claim 16, wherein the disease is associated with transplantation. The use of claim 27, wherein the disease is transplant rejection or graft-versus-host disease. Such as the use of claim 16, wherein the disease is an endocrine disease. Such as the use of claim 29, wherein the endocrine disease is polycystic ovary syndrome, Crouzon’s syndrome or type 1 diabetes. Such as the use of claim 16, wherein the disease is a neurological disease. Such as the use of claim 31, wherein the neurological disease is Alzheimer's disease. The use of claim 15, wherein the disorder is associated with type I interferon, IL-10, IL-12 or IL-23 signaling.